Pyridopyrimidine derivatives, their production and use

ABSTRACT

Pyridopyrimidine derivatives of the formula (A), wherein n denotes an integer of 0 to 3, Q stands for --(CH 2 ) m  --, --O--, --S(O) P  -- or --N--, and R 1  to R 5  stand for substituents, where R 3  is an optionally substituted phenyl, naphthyl, pyridyl, quinolyl, quinolonyl, or thienyl group; or its salt are described. Preparation and use of the derivatives for an antagonistic agent for an endothelin receptor are shown. An endothelin receptor antagonist including the derivative is effective as a therapeutic composition of acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occurring during operation of transplantation of organs. ##STR1##

This application is a continuation of application Ser. No. 08/175,107, filed Dec. 29, 1993, abandoned.

FIELD OF THE INVENTION

This invention relates to novel compounds having condensed heterocyclic ring, which have excellent activities as medicines, i.e. endothelin receptor antagonistic activities, and are useful as vasodilators and therapeutic composition of such diseases as hypertension, acute renal insufficiency, myocardial infarction, angina pectoris and cerebral angiospasm, and a method of producing these compounds.

DESCRIPTION OF THE PRIOR ART

It has been suggested that, among adult diseases increasing in recent years, for example cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency which are caused by ischemia are possibly concerned with endothelin. Endothelin is a peptide consisting of 21 amino acids produced from endothelial cells, and it is obtained as endothelin-1, endothelin-2 and endothelin-3. Hereinafter, in this specification, these endothelin groups are combinedly called "endothelin". It has been reported that endothelin has, among in vivo or synthetic substances which have so far been found, most potent and long-lasting vasoconstrictive action, pressor activity and action of enhancing heart muscle contraction activity. It is considered that the actions of these peptides are performed via endothelin receptor which is considered to exist on smooth muscle membrane of blood vessels etc. As endothelin receptors, have been known endothelin-A receptor and endothelin-B receptor (hereinafter collectively called "endothelin receptor").

Therefore, compounds showing affinity for endothelin receptor while showing endothelin receptor antagonistic activity have prophylactic and therapeutic effects against diseases caused by ischemia, for example, cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency, thus development of these compounds being greatly expected.

As endothelin receptor antagonistic substances, compounds derived from natural source have been obtained, as disclosed in several researchers, for example, Ishimaru et al. [JPA H4(1992)-134048], Fujimoto et al. [Federation of European Biochemical Societies Letters, 305 p.41 (1992)], Oh-hata et al. [JPA H3(1991)-047163], Miyata et al. [JPA H4(1992)-046127] and Yano et al. [JPA H3(1991)-094692].

Further, reports were made by Henmi et al. [EP 457195-A2], Ishikawa et al. [EP 460679-A2 and EP 436189-A], Hashimoto et al. [JPA H3(1992)-130299], Masaki et al. [JPA H3(1992)-024099], G. Hamon et al. [EP 487410-A2], W. L. Cody et al [J. Med. Chem., (1992) 35, p. 3303] and Wakimasu et al. [WO9113089-A, EP499266-A1], that peptide compounds were obtained.

However, when dosage forms of drugs, stability of compounds, durability of pharmacological actions and stability to metabolism are taken into consideration, synthetic endothelin receptor antagonists prepared by non-peptidizing these peptide compounds are strongly desired. Under the present circumstances, however, very few reports are found on non-peptide synthetic endothelin receptor antagonists, for example, a recent report by K. Bali et al. [EP510526-A1].

On the other hand, a 2,4(1H,3H)-dioxopyrido[2,3-d]pyrimidine-8-acetic acid derivative was reported by H. R. Haward et al. [WO92/12979], which has relatively similar structure to the compound of present invention. The substituents of these compounds, however, are apparently different from those of the present invention. Furthermore, it is reported that the former compounds are useful in therapy as aldose reductase inhibitors for the control of certain chronic diabetic complications but have no actions as endothelin receptor antagonists.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel and useful compounds each having a condensed heterocyclic ring, especially novel compounds which can be used as non-peptide synthetic endothelin receptor antagonists, wherby the foregoing problems can be overcome.

It is another object of the present invention to provide a novel compound having endothelin receptor antagonistic properties which is stable as compound and has long-lasting pharmacological properties and metabolic stability.

It is a further object of the present invention to provide a method of producing the compound and an endothelin receptor antagonistic composition.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present inventors have conducted diligent research works to attain the above objects, resulting in finding out that these objects can be achieved by novel pyridopyrimidine derivatives having endothelin receptor antagonistic activities, and thus the present invention has been accomplished based on this finding.

The present invention provides a pyrido[2,3-d]pyrimidine derivative of the formula (A) or a salt thereof; ##STR2## wherein Q is --(CH₂)_(m) -- (m denotes 0 or an integer of 1 to 2), --O--, --S(O)_(p) -- (p denotes 0 or an integer of 1 to 2) or --NH--, and n denotes 0 or an integer of 1 to 3; R¹ and R² independently are hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; R³ is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group; R⁴ is hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, cyano group, --COOR⁶ (R⁶ is hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or an optionally substituted aralkyl group) or --CONR⁷ R⁸ (R⁷ and R⁸ independently are hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or an optionally substituted aralkyl group); R⁵ is hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, --X¹ R⁹ (X¹ is --O--, --NR¹⁰ -- or --S--, R⁹ and R¹⁰ independently are hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group).

As especially preferable examples of the pyridopyrimidine derivative and its salt of this invention, mention is made of the derivative being represented by the following general formula (A') and a salt thereof; ##STR3## wherein n' denotes an integer of 1 to 3; R¹¹ is hydrogen atom, a C₁₋₆ alkyl group, or a C₇₋₁₅ aralkyl group optionally substituted by a C₁₋₆ alkoxy group or C₋₆ alkylthio group; R²¹ is hydrogen atom or a C₁₋₆ alkyl group; R³¹ is a C₆₋₁₅ aryl group optionally substituted by at least one group selected from the group consisting of a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a C₁₋₆ alkoxy group, a halogen atom, nitro group, cyano group and phenyl group, or a 5 to 13-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom optionally substituted by at least one group selected from the group consisting of a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, oxo group and hydroxyl group; R⁴¹ is --COOR⁵¹ (R⁵¹ is hydrogen atom; a C₁₋₆ alkyl group optionally substituted by carboxyl group or a 5 to 10-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; C₃₋₇ cycloalkyl group; or C₆₋₁₅ aralkyl group) or --CONR⁷¹ R⁸¹ (R⁷¹ and R⁸¹ independently are hydrogen atom, C₁₋₆ alkyl group, or C₆₋₁₄ aryl group); R⁵¹ is hydrogen atom, a C₁₋₆ alkyl group, or a C₆₋₁₄ aryl group optionally substituted by a C₁₋₃ alkylenedioxy group.

The present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the formula (A) or a salt thereof, which comprises subjecting a compound represented by the formula (I); ##STR4## wherein n, R¹ and R² are of the same meaning as defined above] or a salt thereof to heating under reflux in a solvent together with a cyclic hydrocarbon or heterocyclic aldehyde represented by the formula R³ Q--CHO (Q and R³ are of the same meaning as defined above) and beta-ketoester, or together with a derivative obtained by subjecting the said aldehyde and ketoester to dehydrative condensation, to give a compound of the formula (B); ##STR5## wherein n, Q, R¹, R², R³, R⁴ and R⁵ are of the same meaning as defined above, or a salt thereof, subjecting the compound (B) or a salt thereof to oxidation with an oxidizing agent to give a compound of the formula (A); ##STR6## wherein n, Q, R¹, R², R³, R⁴ and R⁵ are of the same meaning as defined above, or a salt thereof. Further in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Aa) ##STR7## wherein n, R¹, R³, R⁴, R⁵ and Q are of the same meaning as defined above, or a salt thereof.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned formula (A) or a salt thereof, which comprises subjecting a compound represented by the formula (I) ##STR8## wherein n, R¹ and R² are of the same meaning as defined above, to heating together with a 3,3-bismethylthio derivative in dimethylformamide to give a compound of the formula (C) ##STR9## wherein n, R¹, R², R⁴ and R⁵ are of the same meaning as defined above, or a salt thereof, allowing the compound (C) or a salt thereof to react with a nucleophilic reagent represented by the formula R³ QH (Q and R³ are of the same meaning as defined above) to give a compound of the formula (A); ##STR10## wherein n, Q, R¹, R², R³, R⁴ and R⁵ are of the same meaning as defined above, or a salt thereof. Further in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Aa); ##STR11## wherein n, R¹, R³, R⁴, R⁵ and Q are of the same meaning as defined above, or a salt thereof.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above formula (A) or a salt thereof, which comprises subjecting a compound represented by the formula (II); ##STR12## wherein R¹ is of the same meaning as defined above or a salt thereof to heating under reflux in a solvent together with a derivative represented by the formula QR³ CHCR⁴ COR⁵ (Q, R³, R⁴ and R⁵ are of the same meaning as defined above) obtained by subjecting a cyclic hydrocarbon or heterocyclic aldehyde represented by the formula R³ Q--CHO (Q and R³ are of the same meaning as defined above) and beta-ketoester to dehydrative condensation, to give a compound of the formula (B'); ##STR13## wherein Q, R¹, R³, R⁴ and R⁵ are of the same meaning as defined above, or a salt thereof, subjecting the compound (B') or a salt thereof to oxidation with an oxidizing agent to give a compound of the formula (D); ##STR14## wherein Q, R¹, R³, R⁴ and R⁵ are of the same meaning as defined above; then subjecting the compound (D) or a salt thereof to reacting with a halogenated alkylcarboxylate derivative represented by the formula X² (CH₂)_(n) COOR², wherein X² is a halogen atom, n and R² are of the same meaning as defined above, in an appropriate solvent, in the presence of a base to give a compound of the formula (A) and a salt thereof. Further, in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Aa) or a salt thereof.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned general formula (A) or a salt thereof wherein QR³ is 2-(4-quinolonyl) group and R⁴ is carboxyl group, which comprises heating a compound or its salt, the compound being represented by the formula (E); ##STR15## wherein n, Q, R¹, R² and R⁵ are of the same meaning as defined above, under reflux in a solvent together with thionyl chloride, to give a compound of the formula (Ab); ##STR16## wherein n, Q, R¹, R² and R⁵ are of the same meaning as defined above, or a salt thereof.

Further, in the case where R² is not a hydrogen atom, the said compound (Ab) or a salt thereof may be hydrolyzed to give a compound of the formula (Ac) or a salt thereof; ##STR17## wherein n, R¹ and R⁵ are of the same meaning as defined above.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned general formula (A) or a salt thereof, which comprises reacting a compound or its salt, the compound being represented by the formula (F); ##STR18## wherein n, Q, R², R³, R⁴ and R⁵ are of the same meaning as defined above, with a halogenated alkyl, halogenated aryl or halogenated aralkyl compound represented by the formula R¹ X² wherein X² is a halogen atom, and R¹ is of the same meaning as defined above, in an appropriate solvent, in the presence of a base to give a compound of the formula (A) and a salt thereof. Further, in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Aa) or a salt thereof.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned formula (A) or a salt thereof, wherein R⁴ is --COOR⁶ ' (R⁶ ' is an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or an optionally substituted aralkyl group, which comprises reacting a compound or its salt, the compound being represented by the formula (G); ##STR19## wherein n, Q, R¹, R², R³ and R⁵ are of the same meaning as defined above, with a halogenated alkyl, a halogenated aryl or halogenated aralkyl compound represented by the formula R⁶ 'X² wherein X² is halogen atom, and R⁶ ' is of the same meaning as defined above, in appropriate solvent, in the presence of a base to give a compound of the formula (A), wherein R⁴ is --COOR⁶ ' (R⁶ ' is of the same meaning as defined above) and a salt thereof. Further, in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Aa) wherein R⁴ is --COOR⁶ ' (R⁶ ' is of the same meaning as defined above) or a salt thereof.

Further, the present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned general formula (A) wherein QR³ is 2-(4-quinolonyl) group and R⁴ is --COOR⁶ or --CONR⁷ R⁸ (R⁶, R⁷ and R⁸ are of the same meaning as defined above) or a salt thereof , which comprises reacting a compound or its salt, the compound being represented by the formula (Ad); ##STR20## wherein n, R² and R⁵ are of the same meaning as defined above, with thionyl chloride in an appropriate solvent, then reacting with a halogenated alkyl, halogenated aryl or halogenated aralkyl compound represented by the formula R¹ X², wherein X² is a halogen atom, and R¹ is of the same meaning as defined above, in an appropriate solvent, in the presence of a base to give a compound of the formula (H) ##STR21## wherein n, R¹, R² and R⁵ are of the same meaning as defined above, or a salt thereof; and then subjecting the compound (H) or a salt thereof to reacting with a nucleophilic reagent, which is capable of incorporating thereinto a substituent represented by --OR⁶ or --NR⁷ R⁸ (R⁶, R⁷ and R⁸ is of the same meaning as defined above), in an appropriate solvent to give a compound of the formula (A) wherein QR³ is 2-(4-quinolonyl) group and R⁴ is --COOR⁶ or --CONR⁷ R⁸ (R⁶, R⁷ and R⁸ are of the same meaning as defined above) and a salt thereof.

Further, in the case where R² is not a hydrogen atom, the said compound (A) or a salt thereof may be hydrolyzed to give a compound of the formula (Ac) wherein QR³ is 2-(4-quinolonyl) group and R⁴ is --COOR⁶ or --CONR⁷ R⁸ (R⁶, R⁷ and R⁸ is of the same meaning as defined above) or a salt thereof.

And, the present invention is to provide an endothelin receptor antagonistic agent containing, as the effective component, a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned formula (A) or a pharmaceutically acceptable salt thereof.

Furthr the present invention is to provide said endothelin receptor antagonistic composition as a therapeutic composition of acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arterial sclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs, especially a therapeutic composition of acute renal insufficiency and/or myocardial infarction.

The compound represented by the formula (A) of this invention (hereinafter referred to as compound [A]) will be described in further detail.

In the formula (A), Q means --(CH₂)_(m) -- (m means 0 or an integer of 1 to 2), --O--, --S(O)_(p) -- (p means 0 or an integer of 1 to 2) or --NH--. Preferably, Q is --(CH₂)_(m) --, especially preferably m is 0 or 1.

The symbol n means 0 or an integer of 1 to 3, preferably n is 1 or 2, especially preferably n is 1.

In the formula (A), R¹ and R² may be the same as or different from each other, and respectively are hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group.

Examples of the C₁₋₆ alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group.

Among them, C₁₋₄ alkyl groups as exemplified by methyl group, ethyl group, propyl group, isopropyl group, butyl group and isobutyl group, for example, are preferable. Methyl group is especially preferable.

The C₁₋₆ alkyl group may have 1 to 3 appropriate substituents, as exemplified by a C₃₋₇ cycloalkyl group, a 5 to 10-membered aromatic heterocyclic group containing 1 to 4 hereto atoms selected from nitrogen atom, oxygen atom and sulfur atom, a 5 to 10-membered non-aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, amino group, a mono-(C₁₋₆ alkyl)amino group, a di(C₁₋₆ alkyl)amino group, amidino group, a C₁₋₆ alkylcarbonyl group, a C₆₋₁₄ arylcarbonyl group, a C₇₋₁₅ aralkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, a C₆₋₁₄ aryloxycarbonyl group, a C₇₋₁₅ aralkyloxycarbonyl group, carbamoyl group, a mono-(C₁₋₆)alkylcarbamoyl group, a di-(C₁₋₆)alkylcarbamoyl group, sulfamoyl group, a mono-(C₁₋₆)alkylsulfamoyl group, a di-(C₁₋₆)alkylsulfamoyl group, carboxyl group, hydroxyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, a C₃₋₇ cycloalkyloxy group, a C₆₋₁₄ aryloxy group, a C₇₋₁₅ aralkyloxy group, mercapto group, a C₁₋₆ alkylthio group, a C₆₋₁₄ arylthio group, a C₇₋₁₅ aralkylthio group, sulfo group, cyano group, azido group, nitro group, nitroso group or a halogen atom.

In the present invention, the aryl group means monocyclic or condensed polycyclic aromatic hydrocarbon groups, as exemplified by C₆₋₁₄ aryl group such as phenyl group, naphthyl group, anthryl group, phenanthryl group and acenaphthylenyl group, especially preferable ones being phenyl group, 1-naphthyl group and 2-naphthyl group.

The aryl group may have one or more, preferably 1 to 3 appropriate substituents, as exemplified by a C₁₋₆ alkyl group (e.g. methyl group, ethyl group and propyl group), C₂₋₆ alkenyl group (e.g. vinyl group, allyl group and 2-butenyl group), C₂₋₆ alkynyl group (e.g. propargyl group and 2-butynyl group), a cycloalkyl group (e.g. a C₃₋₇ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group), C₆₋₁₄ aryl group (e.g. phenyl group and naphthyl group), aromatic heterocyclic group (e.g. a 5 to 9-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, as exemplified by furyl group, thienyl group, pyrrolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, quinolyl group and quinolonyl group), non-aromatic heterocyclic group (e.g. a 5 to 9-membered non-aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, as exemplified by oxiranyl group, azetidinyl group, oxetanyl group, thiethanyl group, pyrrolidinyl group, teterahydrofuryl group, thiolanyl group, piperidyl group, tetrahydropyranyl group, morphonyl group, thiomorphonyl group and piperazinyl group), aralkyl group (e.g. a C₇₋₁₅ aralkyl group such as benzyl group, phenylethyl group, 1-naphtylmethyl, 1-naphthylethyl), amino group, N-monosubstituted amino group (e.g. C₁₋₆ monoalkylamino group such as methylamino group, ethylamino group and propylamino group), N,N-disubstituted amino group (e.g. N,N-disubstituted amino group substituted with a C₁₋₆ alkyl group, as exemplified by dimethyl amino group and diethylamino group), amidino group, acyl group (e.g. a C₁₋₈ alkylcarbonyl group such as formyl group, acetyl group, propionyl group and butyryl group; a C₆₋₁₄ arylcarbonyl group such as benzoyl group; a C₇₋₁₅ aralkylcarbonyl group such as benzylcarbonyl group, phenylethylcarbonyl group, a C₁₋₈ alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; a C₆₋₁₄ aryloxycarbonyl group such as phenyloxycarbonyl group alpha-naphthylcarbonyl group and a C₇₋₁₅ aralkyloxycarbonyl group such as benzyloxycarbonyl group, 1-naphthyloxycarbonyl group), carbamoyl group, N-monosubstituted carbamoyl group (e.g. a C₁₋₆ alkylcarbamoyl group such as methylcarbamoyl group, ethylcarbamoyl group and propylcarbamoyl group), N,N-disubstituted carbamoyl group (e.g. N,N-disubstituted carbamoyl group substituted with a C₁₋₆ alkyl group, as exemplified by dimethylcarbamoyl group and diethylcarbamoyl group), sulfamoyl group, N-monosubstituted sulfamoyl group (e.g. N-alkylsulfamoyl group having a C₁₋₆ alkyl group, as exemplified by methylsulfamoyl group, ethylsulfamoyl group and propylsulfamoyl group), N,N-disubstituted sulfamoyl group (e.g. N,N-dialkyl substituted sulfamoyl group having a C₁₋₆ alkyl group, as exemplified by dimethylsulfamoyl group and diethylsulfamoyl group), carboxyl group, hydroxyl group, a C₁₋₆ alkxoy group (e.g. methoxy group, ethoxy group and propoxy group), a C₂₋₆ alkenyloxy group (e.g. vinyloxy group and allyloxy group), cycloalkyloxy group (e.g. a C₃₋₇ cycloalkyloxy group such as cyclopropyloxy group), aralkyloxy group (e.g. a C₇₋₁₄ aralkyloxy group such as benzyloxy group, 1-naphthyloxy group), aryloxy group (e.g. C₆₋₁₄ aryloxy group such as phenyloxy group and naphthyloxy group), mercapto group, a C₁₋₆ alkylthio group (e.g. methylthio group, ethylthio group and propiothio group), aralkylthio group (e.g. a C₇₋₁₅ aralkylthio group such as benzylthio group, 1-naphthylthio group,), arylthio group (e.g. a C₆₋₁₄ arylthio group such as phenylthio group and naphthylthio group), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom and iodine atom), a C₁₋₃ alkylenedioxy group (e.g. methylenedioxy group, ethylenedioxy group) among others.

Said aralkyl group means an alkyl group having an aryl group as substituent (arylalkyl group), and said aryl group is preferably the same as the above-mentioned aryl group, and as a preferable alkyl group, a C₁₋₆ alkyl groups is mentioned. A preferable aralkyl group includes, a C₇₋₁₅ aralkyl group, for example, benzyl group, phenethyl group, 3-phenylpropyl group, (1-naphthyl)methyl group and (2-naphthyl)methyl group, especially preferable one being a phenyl-(C₁₋₃) alkyl group such as benzyl group and phenethyl group.

The aryl group in the aralkyl group may have the same substituents as those which the the above-mentioned aryl group may have, and said substituent is preferably a C₁₋₆ alkoxy group (e.g. methoxy group, ethoxy group or propoxy group), a C₁₋₆ alkylthio group (e.g. methylthio group, ethylthio group or propylthio group ), especially preferable ones being a C₁₋₃ alkoxy group such as methoxy group.

Preferable examples of R¹ include hydrogen atom, a C₁₋₆ alkyl group (e.g. methyl group, ethyl group), a C₇₋₁₅ aralkyl group optionally substituted by a C₁₋₆ alkoxy group or a C₁₋₆ alkylthio group (especially preferable one being a phenyl-(C₁₋₃) alkyl group optionally substituted by a C₁₋₆ alkoxy group or a C₁₋₆ alkylthio group).

Preferable examples of R² include hydrogen atom, a C₁₋₆ alkyl group (e.g. methyl group, ethyl group, propyl group or isopropyl group).

In the formula (A), R³ means an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and said cyclic hydrocarbon group is exemplified by an aryl group or cycloalkyl group. Said aryl group means the same ones as described referring to R¹ and R², which may have, like the aryl group of R¹ and R², one or more, preferably 1 to 3, appropriate substituents. As said substituent, mention is made of the same ones as described referring to the aryl group of R¹ and R². Especially preferable sustituent includes a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a C₁₋₆ alkoxy group, cyano group, nitro group, a halogen atom and phenyl group.

Examples of said cycloalkyl group include a C₃₋₁₀ cycloalkyl group or a C₃₋₁₀ bicycloalkyl group, as exemplified by cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, bicyclo[2,2,1]heptyl group, bicyclo[2,2,2]octyl group, bicyclo[3,2,1]octyl group, bicyclo[3,2,1]nonyl group, bicyclo[4,2,1]nonyl group and bicyclo[4,3,1]decyl group. Preferable example of said cycloalkyl group includes a C₄₋₇ cycloalkyl group (e.g. cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group). Said cycloalkyl group may have 1 to 3, appropriate substituents such as a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, carboxyl group, hydroxyl group, nitro group or a halogen atom.

Examples of said heterocyclic group include a 5 to 13-membered aromatic heterocyclic group having, as an atom constituting the ring, 1 to 4 hetero atoms selected from O, S and N, or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).

Preferable examples of said heterocyclic group include aromatic monocyclic heterocyclic groups such as furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, furazanyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and triazinyl group; and aromatic condensed heterocyclic groups such as benzofuranyl group, isobenzofuranyl group, benzo[b]thienyl group, indolyl group, isoindolyl group, 1H-indazolyl group, benzoimidazolyl group, benzoxazolyl group, 1,2-benzoisoxazolyl group, benzothiazolyl group, 1,2-benzoisothiazolyl group, 1H-benzotriazolyl group, quinolyl group, quinoline-N-oxide-2-yl group, quinoline-N-oxide-3-yl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, carbazolyl group, alpha-carbolinyl group, beta-carbolinyl group, gamma-carbolinyl group, acrydinyl group, phenoxazinyl group, phenothiazinyl group, phenazinyl group, phenoxathiinyl group, thianthrenyl group, phenanthridinyl group, phenanthrolinyl group, indolizinyl group, pyrrolo[1,2-b]pyridazinyl group, pyrazolo[1,5-a]pyridyl group, imidazo[1,2-a]pyridyl group, imidazo[1,5-a]pyridyl group, imidazo[1,2-b]pyridazinyl group, imidazo[1,2-a]pyrimidinyl group, 1,2,4-triazolo[4,3-a]pyridyl group and 1,2,4-triazolo[4,3-b]pyridazinyl group. An especially preferable example is pyridyl group, quinolyl group, quinoline-N-oxide-2-yl group, quinoline-N-oxide-3-yl group, benzofuranyl group, benzo[b]thienyl group or thienyl group.

Preferable examples of said non-aromatic heterocyclic group include oxiranyl group, azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, tetrahydrofuryl group, thiolanyl group, piperidyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group and piperazinyl group.

And, said heterocyclic group may have one or more, preferably 1 to 3, appropriate substituents, which are the same ones as mentioned referring to the aryl group of R¹ and R². Among them, a C₁₋₆ alkyl group is preferable.

Preferable examples of R³ include a C₆₋₁₄ aryl group (e.g. phenyl group, naphthyl group) optionally substituted by at least one selected from the group consisting of C₁₋₆ alkyl groups, C₃₋₇ cycloalkyl groups, C₁₋₆ alkoxy groups, halogen atoms, nitro group, cyano group and phenyl group; or a 5 to 13-membered aromatic heterocyclic group containing 1 to 4 hereto atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g. pyridyl group, quinolyl group, quinoline-N-oxide-2-yl group, quinoline-N-oxide-3-yl group, benzofuranyl group, benzo[b]thienyl group, thienyl group) optionally substituted by at least one selected from the group consisting of C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, oxo group and hydroxyl group. Among them, phenyl group, naphthyl group, pyridyl group, quinolyl group, thienyl group, quinoline-N-oxide-2-yl group, quinoline-N-oxide-3-yl group, benzofuranyl group, methylbenzo[b]thienyl group and 4-quinolonyl group (e.g. 2-(4-quinolonyl group)) are especially preferable as R³. The 4-quinolonyl group is a quinolyl group substituted by oxo group at 4-position.

In the formula (A), R⁴ is hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, cyano group, --COOR⁶ (R⁶ stands for hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or aralkyl group) or --CONR⁷ R⁷ (R⁷, R⁸ independently stand for hydrogen, an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or aralkyl group).

Said C₁₋₆ alkyl group, aryl group and aralkyl group are the same ones as mentioned referring to R¹ and R², and said cyclic hydrocarbon group means the same ones mentioned referring to R³. Said C₁₋₆ alkyl group, aryl group, aralkyl group and cyclic hydrocarbon group may have, like in the cases of R¹, R² and R³, one or more, preferably 1 to 3, appropriate substituents, which are the same ones as described referring to R¹, R² and R³.

Preferable examples of R⁴ include --COOR⁶ or --CONR⁷ R⁸, wherein R⁶ is preferablly a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group or a C₇₋₁₅ aralkyl group which can optionally be substituted by hydrogen atom, carboxyl group or a 5 to 10-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; and R⁷ and R⁸ are respectively hydrogen atom, a C₁₋₆ alkyl group or a C₆₋₁₄ aryl group. Especially preferable examples of R⁶ is a C₁₋₆ alkyl group substituted by quinolyl group.

Preferable examples of --CONR⁷ R⁸ include a carbamoyl group or a carbamoyl group substituted by a C₁₋₆ alkyl group.

In the formula (A), R⁵ stands for hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or --X¹ R⁹ (X¹ stands for --O--, --NR¹⁰ -- or --S--; R⁹ and R¹⁰ independently stand for hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group). The C₁₋₆ alkyl group, aryl group and aralkyl group in R⁵, R⁹ and R¹⁰ are the same ones as mentioned referring to R¹ and R², and said aryl group and aralkyl group may have, like in the cases of R¹, R² and R³, one or more, preferably 1 to 3, appropriate substituents. As those substituents, mention is made of the same ones as described referring to R¹ and R².

Preferable examples of R⁵ include hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aryl group, especially preferable ones being hydrogen atom, a C₁₋₆ alkyl group (e.g. methyl group, ethyl group, propyl group, isopropyl group and isobutyl group) or a C₆₋₁₄ aryl group (e.g. phenyl group) optionally substituted by C₁₋₃ alkylenedioxy group.

Preferable examples of the compound [A] of this invention include the compound wherein n denotes an integer of 1 to 3; R¹ is hydrogen atom, a C₁₋₆ alkyl group, or a C₇₋₁₅ aralkyl group optionally substituted by a C₁₋₆ alkoxy group or C₁₋₆ alkylthio group; R² is hydrogen atom or a C₁₋₆ alkyl group; QR³ is a C₆₋₁₄ aryl group optionally substituted by at least one selected from the group consisting of C₁₋₆ alkyl groups, C₃₋₇ cycloalkyl groups, C₁₋₆ alkoxy groups, halogen atoms, nitro group, cyano group and phenyl group; or a 5 to 13-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom optionally substituted by at least one selected from the group consisting of C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, oxo group and hydroxyl group; R⁴ is --COOR⁶¹ (R⁶¹ is hydrogen atom, a alkyl group optionally substituted by carboxyl group or a 5 to 10-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; C₃₋₇ cycloalkyl group; or 6-15 aralkyl group) or --CONR⁷¹ R⁸¹ (R⁷¹ and R⁸¹ independently are hydrogen atom, C₁₋₆ alkyl group, or C₆₋₁₄ aryl group); R⁵ is hydrogen atom, a C₁₋₆ alkyl group, or a C₆₋₁₄ aryl group optionally substituted by a C₁₋₃ alkylenedioxy group. An especially preferable example is the one wherein the 5 to 13-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom of R³ is selected from the group consisting of pyridyl group, quinolyl group, quinoline-N-oxide-2-yl group, quinoline-N-oxide-3-yl group, benzofuranyl group, benzo[b]thienyl group and thienyl group; and the 5 to 10-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom of R⁶¹ is quinolyl group.

The specific examples of preferable compound of this invention, include 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidin-3-acetic acid, 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic acid, ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid and their salts.

As salts of the compound [A] of this invention, pharmaceutically acceptable acid addition salts are mentioned as especially preferable ones. As such salts, use is made of, for example, those with an inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid or sulfuric acid) or those with an organic acid (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid). And, in the case where the compound [A] of this invention has an acid group such as --COOH, the compound [A] may form a salt with an inorganic base (e.g. an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g. trialkylamine having a C₁₋₈ alkyl groups, such as triethylamine).

As salts of the starting compounds for producing the compound [A] of this invention, use is made of, for example, salts with an inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid or sulfuric acid) or salts with an organic acid (e.g. (acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid). And, in the case where the starting compound has an acid group such as --COOH, it may form a salt with an inorganic base (e.g. an alkali metal or alkaline earth metal such as sodium potassium, calcium or magnesium; or ammonia) or an organic base (e.g. trialkylamine having a C₁₋₈ alkyl group, such as triethylamine).

The compound [A] of this invention and salts thereof can be readily produced by per se known methods, and, as typical ones, the following seven methods are mentioned.

[Production Method--1]

A urea derivative (i) represented by the formula R¹ 'NHCONH₂ (R¹ ' stands for an optionally substituted C₁₋₆ alkyl group, aryl group or aralkyl group), which is synthesized from a C₁₋₆ alkylamine, arylamine or aralkylamine is heated in an appropriate solvent such as ethyl alcohol in the presence of a cyanoacetic acid derivative and a base, at the temperature of 80°-120° C. for 2-240 hours, preferablly 24-100 hours, to give a 1-(C₁₋₆ alkyl)substituted, 1-aryl-substituted or 1-aralkyl-substituted 6-aminopyrimidine-2,4(1H,3H)-dione derivative (ii).

This compound is stirred, together with a halogenated acetic acid ester derivative or a halogenated propionic acid ester derivative, in the presence of a base in an appropriate solvent such as dimethylacetamide or dimethylformamide at the temperature of 40°-70° C., usually for 4-96 hours, preferablly 12-24 hours, to give a 6-amino-2,4(1H,3H)-dioxopyrimidine-3-acetic acid ester derivative or a 6-amino-2,4(1H,3H)-dioxopyrimidine-3-propionic acid ester derivative represented by the formula (I').

The derivative (I') thus obtained is, in accordance with the Hantzsch's synthetic method [A. Hantzsch, Ann. Chem. 215, 1 (1882)], subjected to heating with arylaldehyde and beta-keto ester under reflux at the temperature of 80°-100° C., usually for 2-240 hours, preferablly 12-120 hours, in an appropriate solvent such as ethyl alcohol, or subjected beforehand to Knoevenagel condensation reaction [T. Yamamori, Y. Hiramatsu, K. Sakai and I. Adachi, Tetrahedron, 41, 913 (1985)] to synthesize a dehydrated condensed derivative with arylaldehyde and beta keto ester, then the dehydrated condensed derivative and the derivative (I') are heated under reflux at the temperature of 100°-130° C., usually for 2-240 hours, preferablly 12-120 hours, in an appropriate solvent such as toluene to give 5,8-dihydropyrido[2,3-d]pyrimidine-2,4-dione derivative (B1). This compound (B1) is subjected to oxidation with an appropriate oxidizing agent such as sodium nitrite in acetic acid to give the compound (A1) of this invention. Further, if necessary, the compound (A1) is subjected to an appropriate conditions, for example, alkali hydrolysis in an appropriate solvent such as methanol, ethanole, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at the elevated temperature (e.g. 40°-100° C.), usually for 2-48 hours, preferablly 2-24 hours.

The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. ##STR22##

[Production Method--2]

In accordance with an analogous method to that reported by Y. Tominaga et al. [Chim. Pharm. Bull., 32, 122 (1984)], 6-amino-2,4(1H,3H)-dioxopyrimidine-3-acetic-acid ester derivative (I') is heated with a 3,3-bismethylthio derivative in dimethylformamide, at the temperature of 100°-150° C., usually for 1-12 hours, preferablly 2-6 hours, to give a pyrido[2,3-d]pyrimidine-2,4-dione derivative (C1). A nucleophilic reagent represented by the formula R³ QH (R³ and Q are of the same meaning as defined above) is allowed to react with the compound (C1), at the temperature of 40°-100° C., usually for 2-120 hours, preferablly 2-24 hours, in an appropriate solvent (e.g. methanol, ethanol, tetrahydrofuran, dioxane or dimethylformamide), to give the compound (A1) of this invention.

Further, if necessary, the compound (A1) is subjected to an appropriate conditions, for example, alkali hydrolysis in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at the elevated temperature (e.g. 40°-100° C.), usually for 2-48 hours, preferablly 2-24 hours. The above reactions are collectively shown in the following reaction scheme, in which R¹ ' is an optionally substituted C₁₋₆ alkyl group, aryl group or aralkyl group and each symbol except R¹ ' is of the same meaning as defined above. (0029)

[Production Method--2] ##STR23## [Production Method--3]

A 1-(C₁₋₆ alkyl) substituted, 1-aryl-substituted or 1-aralkyl-substituted 6-aminopyrimidine-2,4(1H,3H)-dione derivative (ii) is, in accordance with forementioned Hantzsch's synthetic method [A. Hantzsch, Ann. Chem. 215, 1 (1882)], subjected to heating with a dehydrated condensed derivative of an aldehyde derivative with a beta-keto ester derivative, at a temperature of 40°-120° C., usually for 0.5-4 hours, preferably 0.5-1 hour, in an appropriate solvent (e.g. dimethylacetamide, dimethylsulfoxide, dimethylformamide) to give a compound (D1).

The dehydrated condensed derivative is previously obtained by heating an aldehyde derivative (e.g. quinoline-2-carboxyaldehyde) with a beta keto ester (e.g. ethyl isobutylylacetate, 2-cyanoethyl isobutylylacetate) under reflux in an appropriate solvent (e.g. benzene, toluene) in the presence of an appropriate catalyst (e.g. pyrrolidine and acetic acid, piperidine and acetic acid) at a temperature of 100°-120° C. for usually 0.5-1 hour.

This compound (Di) is subjected to oxidation with an appropriate oxidizing agent such as sodium nitrite in acetic acid, in an appropriate solvent such as acetic acid, for usually 0.25-24 hours, preferably 1-12 hours, to give the compound (D2). The compound (D2) thus obtained, is allowed to stir with a halogenated acetic acid-ester derivative or a halogenated propionic acid-ester derivative, in the presence of a base (e.g. sodiumu hydride, potassium carbonate), in an appropreate solvent (e.g. dimethylacetamide, dimethylformamide), at room temperature or at an elevated temperature such as 40°-120° C., for usually 0.5-12 hours, preferably 0.5-2 hours to give the compound (A1), 3-position acetic acid ester or propionic acid ester derivative, of this invention.

Further, if necessary, the compound (A1) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-12 hours.

The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. ##STR24##

[Production Method--4]

Here is an example of changing the substituent in the compound of this invention.

A 5-(2-quinolyl)-6-cyanoethoxycarbonyl derivative (E1) is subjected to stirring in an appropriate solvent (e.g. methanol, ethanol, tetrahydrofuran or dioxane) in the presence of an appropriate weak base (e.g. aqueous solution of sodium carbonate or sodium hydrogen carbonate), at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-12 hours, preferably 0.5-2 hours to give a 6-carboxyl derivative (E2).

The compound (E2) is dissolved in an appropriate solvent (e.g. methylene chloride, carbon tetrachloride, 1,2-dichloroethane or toluene) and subjected to heating and reacting with much excess of thionyl chloride (e.g. 10 times of equivalent) under reflux (e.g. 40°-120° C.) for usually 5-120 minutes, preferably 5-60 minutes. The reaction mixture was then concentrated to dryness while removing the excess of thionyl chloride. The residue is dissolved in an appropriate solvent (e.g. acetonitrile, tetrahydrofuran, dioxane or dimethylacetamide). Being added an appropreate weak base (e.g. aqueous solution of sodium carbonate or sodium hydrogen carbonate), the solution is subjected to stirring at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-48 hours, preferably 2-24 hours to give 4-quinolonyl derivative (A3).

Further, if necessary, the compound (A3) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A4) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-12 hours.

The reactions in the above-described production method are collectively shown by the following reaction scheme, in which R² ' is an optionally substituted C₁₋₆ alkyl group, aryl group or aralkyl group and each symbol except R² ' is of the same meaning as defined above.

[Production Method-4] ##STR25## [Production Method--5]

A 1-(2,4-dimethoxybenzyl) derivative (F1) is subjected to oxidizing to give 1-hydro derivative (F). The oxidization is carried out as follows.

The compound (F1) is dissolved in an appropriate solvent (e.g. an aqueous solution of acetone or acetonitrile), to which an appropriate oxidizing agent such as cerium ammonium nitrate (CAN) is added, and the mixture is allowed to stir at room temperature or at an elevated temperature (e.g. 40°-60° C.), usually for 0.5-2 hours, preferably 0.5-1 hour to give the compound (F).

Another method of oxidization comprises stirring the compound (F1) in trifluoroacetic acid (TFA) at a temperature of 40°-80° C., usually for 1-12 hours, preferably 2-6 hours to give the compound (F). The compound (F) thus obtained is subjected to reacting by stirring with a halogenated lower alkyl derivative (e.g. methyl iodide) or a halogenated aralkyl derivative (e.g. substituted benzyl chloride derivative or substituted benzyl bromide derivative) in an appropriate solvent (e.g. dimethylacetamide, dimethylformamide, acetone or tetrahydrofuran) in the presence of an appropriate base (e.g. sodium hydride or pottasium carbonate), usually for 0.5-4 hours, preferably 0.5-2 hours to give the compound (A).

Further, if necessary, the compound (A) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (Aa) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature (e.g. 40°-100° C.).

The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above.

[Production Method--5] ##STR26## [Production Method--6]

Here is an example of the process for producing the compound (A) of this invention wherein the substituent at 6-position is --COOR⁶ ' (R⁶ ' is an optionally substituted C₁₋₆ alkyl group, an optionally substituted cyclic hydrocarbon group or an optionally substituted aralkyl group).

The compound (A9), whose substituent at 6-position is COOH, is subjected to stirring with a halogenated alkyl, a halogenated cyclic hydrocarbon or halogenated aralkyl derivative (e.g. ethyl bromide, isobutyl bromide or benzyl bromide) in an appropriate solvent (e.g. dimethylacetamide or dimethylformamide) in the presence of an appropriate weak base (e.g. potassium carbonate, triethylamine or sodium hydrogen carbonate), usually for 2-48 hours, preferably 2-24 hours to give a compound (A10) of this invention whose substituent at 6-position is --COOR⁶ '.

Further, if necessary, the compound (A10) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane, or acid hydrolyzing in an appropriate solvent such as methylene chloride to give the compound (A11) of this invention.

The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst (e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-48 hours, preferably 2-24 hours.

The acid hydrolysis reaction can be carried out by stirring the reaction mixture with a catalytic amount or excessive amount of an appropriate acid such as trifluoroacetic acid, at room temperature or at an elevated temperature (e.g. 40°-100° C.), usually for 2-48 hours, preferably 2-24 hours.

The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. ##STR27##

[Production Method--7]

Here is an example of the process for producing the compound (A) of this invention wherein the substituent at 5-position is 2-(4-quinolonyl) group and at 6-position is --COOR⁶ or --CONR⁷ R⁸ (R⁶, R⁷ and R⁸ are independently hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted aralkyl group).

The compound (A12), whose substituent at 1-position is hydrogen atom, is subjected to stirring with excess of thionyl chloride (e.g. 5-20, preferably 5-10 times of equivalent) in an appropriate solvent (e.g. methylene chloride or toluene) at room temperature or at an elevated temperature (e.g. 40°-60° C.), usually for 0.5-2 hours, preferably 0.5-1 hour. The reaction mixture is then concentrated to dryness under reduced pressure. The residue is dissolved in an appropriate solvent (e.g. methylene chloride). Filtered off the insoluble material (e.g. by filtration with sellaite), the filtrate is concentrated to dryness, and if necessary washed with an appropriate solvent (e.g. ethyl acetate), to give the compound (H1).

The compound (H1) thus obtained is dissolved in an appropriate solvent (e.g. dimethylformamide, dimethylacetamide or acetonitrile), and then is subjected to stirring with usually 1-3, preferably 1-1.5 times of equivalent of an appropriate halogenated alkyl derivative or halogenated aralkyl derivative (e.g. 2-methylthiobenzyl chloride or 2,3-dimethoxybenzyl chroride etc.) in the presence of usually 1-3, preferably 1.5-2 times of equivalent of an appropriate base (e.g. potassium hydrogencabonate, pottasium carbonate or sodium hydride ), at room temperature or at an elevated temperature (e.g. usually 40°-100° C., preferably 40°-60° C.) usually for 2-48 hours, preferably 24-48 hours to give the compound (H2).

After refining by appropriate method (e.g. silica gel column chromatography), if necessary the compound (H2) is dissolved in an appropriate solvent (e.g. acetonitrile or dimethylacetamide), and then is subjected to stirring with excess (usually 5-30, preferably 5-10 times of equivalent) of a nucleophilic reagent (e.g. 2N aqueous solution of pottasium carbonate, aqueous ammonia or an amine compound) at room temperature or at an elevated temperature (e.g. usually 40°-120° C., preferably 40°-80° C.) usually for 1-6 hours, preferably 1-2 hours to give the compound (A13). The reactions in the above-described production method are collectively shown by the following reaction scheme, in which R is --OR⁶ or --NR⁷ R⁸ and each symbol except R is of the same meaning as defined above. ##STR28##

In the above-described [Production Method--1] and [Production Method--2], the compound [A] wherein R¹ =H can be produced by, using a compound represented by R¹ "NH₂ (R¹ " stands for a protective group of ammonia) instead of the starting compound R¹ 'NH₂ (R¹ ' is of the same meaning as defined above), then removing the protecting group shown by R¹ " adequately during or after the reaction.

In the above-described [Production Method--3], the compound [A] wherein R¹ =H can be produced by, using a compound (ii) having R¹ ' (R¹ ' stands for a protective group of ammonia) instead of R¹ ' (R¹ ' is of the same meaning as defined above), then removing the protecting group shown by R¹ " adequately during or after the reaction.

The compound R¹ "NH₂ can be produced by a per se known method or an analogous method thereto, or is commercially available.

For removing the protective group, a per se known method or a method analogous thereto can be employed, for example, by the use of an acid, a base, an oxidizing agent, a reducing agent, ultraviolet ray, hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.

The starting compounds, C₁₋₆ alkylamine, arylamine and aralkylamine can be produced by a per se known method or an analogous method thereto.

The compound [A] thus obtained or a salt thereof can be isolated and purified in conventional manner, e.g. by recrystallization, distillation or chromatography. When the compound [A] is thus obtained as a free compound, it can be converted to a corresponding salt by a per se known method or an analogous method thereto, and, when the compound [A] is obtained as a salt, it can be converted to a free compound or any other salt by a per se conventional method or an analogous method thereto.

In the case where the compound [A] or a salt thereof is an optically active compound, it can be isolated into d-isomer and l-isomer by a conventional means for optical resolution.

The compound [A] or its salt of this invention has excellent endothelin receptor antagonistic activity, therefore, it can be used as endothelin receptor antagonist for warm-blooded animals (e.g. rat, mouse, guinea pig, chicken, dog, cat, sheep, pig, bovine, monkey, man and others).

Moreover, because of its excellent endothelin receptor antagonistic activity, the compound [A] or its salt of this invention can be used as prophylactic and therapeutic composition against cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency.

The compound [A] or its salt of this invention is of a salty and low toxycity.

When the compound [A] or its salt of this invention is used as endothelin receptor antagonist or as prophylactic and therapeutic agents against acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs.

They can be administered either orally or non-orally. Usually, they are administered orally in a form of a solid preparation such as tablets, capsules, granules or powder, or non-orally in a form of intravenous, subcutaneous or intramuscular injection, suppositories or sublingual tablets. Dosage amounts will vary with degrees of symptoms; ages of patients, sex, body weight, difference in sensitivity; administration time; interval, quality of medicinal preparations, preparation, kinds; kinds of effective components, among others, and they are not specifically limited. Usually, the dosage for adult per day ranges from about 0.1 to 500 mg, preferably from about 1 to 100 mg, more preferably from 5 to 50 mg, in one to 4 divided doses per day.

The compounds of this invention can be administered orally or non-orally, formulated with pharmaceutically acceptable carriers, as a solid preparation including tablets, capsules, granules and powder, or as a liquid preparation such as syrup or injections.

The above-mentioned pharmaceutically acceptable carriers include conventional organic or inorganic carriers employed in the field of pharmaceutical preparations; namely, excipients, lubricants, binders and disintegrators in solid preparations; solvents, solubilizers, suspending agents, isotonizers, buffer agents and local anesthetics in liquid preparations. Upon necessity, additives such as preservatives, antioxidants, colorants, sweeteners or the like can also be employed.

Preferable excipients are exemplified by lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicic acid anhydride.

Preferable lubricants are exemplified by magnesium stearate, calcium stearate, talc and colloidal silica.

Preferable binders are exemplified by crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone.

Preferable disintegrators are exemplified by starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, closcarmellose sodium and carboxymethyl starch sodium.

Preferable solvents are exemplified by distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.

Preferable solubilizers are exemplified by polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Preferable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.

Preferable isotonizers are exemplified by sodium chloride, glycerin and D-mannitol.

Preferable buffer agents are exemplified by buffer solutions such as phosphates, acetates, carbonates and citrates.

Preferable local anesthetics are exemplified by benzyl alcohol.

Preferable preservatives are exemplified by para-hydroxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Preferable antioxidants are exemplified by sulfite and ascorbic acid.

By the addition of a suspending composition, a solubilizer, a stabilizing composition, an isotonizer, a preservative or the like to the compound of this invention, intravenous, subcutaneous and intramuscular injections are prepared by conventional methods. Upon necessity, these injections can be made into lyophilized preparations.

EXAMPLES

The following examples are given for the purpose of illustration and not by any of limitation.

Reference Example 1 Production of 2-methoxybenzyl Urea (Chemical Formula 1) ##STR29##

To an aqueous solution (13 ml) containing 2-methoxybenzylamine (13.7 g, 0.1 mol.) was added dropwise dilute sulfuric acid (prepared from 2.8 ml of conc. sulfuric acid and 6.7 ml of refined water) at room temperature. After completion of the dropwise addition, an aqueous solution (70 ml) containing sodium cyanate (7.65 g, 0.12 mol.) was added to the reaction mixture at room temperature taking 15 minutes. The suspension obtained as reaction mixture was heated at 80° C. for one hour. The reaction mixture was cooled, then resulting crystalline precipitates were collected by filtration, followed by recrystallization from ethanol to give 17 g (yield 94%) of colorless prisms.

Reference Example 2 Production of 6-amino-1-(2-methoxybenzyl)pyrimidine-2,4 (1H,3H)-dione (Chemical Formula 2) ##STR30##

A mixture of the compound (10.8 g, 60 mmol.) obtained in Reference Example 1, ethyl cyanoacetate (7.0 g, 62 mmol.) and sodium methoxide (28% methanol solution, 12.0 g, 62 mmol.) was heated for 72 hours in ethanol (100 ml) under reflux. The reaction mixture was cooled, which was then concentrated to dryness. To the concentrate was added a saturated aqueous solution of ammonium chloride (50 ml). The mixture was stirred, then the pH thereof was adjusted to a range of 6 to 7 with 1N HCl.

Resulting precipitates were collected by filtration and recrystallized from a mixture of ethanol and methanol (1:1) to give 10.0 g (yield 68%) of pale yellow prisms, m.p. 278° to 279° C. The elemental analysis values were as shown in Table 1.

                  TABLE 1                                                          ______________________________________                                         Elemental Analysis for C.sub.12 H.sub.13 N.sub.3 O.sub.3                              C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   58.29         5.30    16.99                                           Found    58.00         5.36    17.01                                           ______________________________________                                    

Reference Example 3

The method described as Reference Example 1 and 2 was repeated, while employing various substituted amino compounds in place of 2-methoxybenzylamine. The compounds represented by chemical formula (3) thus obtained were collectively shown in the following Table 2. ##STR31##

                  TABLE 2                                                          ______________________________________                                         Ref. Ex. 3 1-substituent   m.p.                                                Cpd. No.   (R.sup.1)       (°C.)                                        ______________________________________                                         1          2,4-dimethoxybenzyl                                                                            powder()                            2          3-methoxybenzyl 290-294                                             3          3,4-methylenedioxybenzyl                                                                       290-298                                             4          2-methoxyphenyl 288-290                                             ______________________________________                                          () powder:noncrystalline powder (the same in the followin      table)                                                                   

Reference Example 4 Production of Ethyl [6-amino-2,4(1H,3H)-dioxo-1-(2-methoxybenzyl)]pyrimidine-3-acetate (Chemical Formula 4) ##STR32##

A mixture of the compound (6.65 g, 27 mmol.) obtained in Reference Example 2, ethyl bromoacetate (15.0 g, 90 mmol.) and potassium carbonate (16.6 g, 120 mmol.) was stirred in dimethylformamide (500 ml) for 72 hours at 60° C. The reaction mixture was, after cooling, concentrated to dryness, to which were added a saturated aqueous solution of ammonium chloride (30 ml) and ethyl acetate (50 ml), then the mixture was stirred. The organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate (50 ml). The extract was combined with the organic layer, which was then dried. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 3.5 g (yield 39%) of a yellow amorphous product.

The NMR spectrum of thus obtained yellow amorphous compound was as follows.

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 1.27(3H, t), 3.93(3H,s), 4.21(2H,q), 4.70(2H,s), 4.91(1H,s), 5.12(2H,s), 5.31(2H,s), 6.91-7.03(2H,m), 7.27-7.40(1H,m), 7.50-7.55(1H,m).

Reference Example 5 Production of Ethyl [5,8-dihydro-2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 5) ##STR33##

The compound (0.5 g, 1.5 mmol.) obtained in Reference Example 4 was heated for 90 hours under reflux in ethanol (10 ml) together with p-tolualdehyde (0.54 g, 4.5 mmol.) and ethyl isobutyryl acetate (0.71 g, 4.5 mmol.). The reaction mixture was cooled, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.2 g (yield 23%) of a yellow amorphous product. The NMR spectrum of thus obtained amorphous compound are as follows.

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.80(3H,d), 1.06(3H,d), 1.25(3H,t), 1.26(3H,s), 2.25(3H,s), 3.58(1H,m), 3.96(3H,s), 4.12(2H,q), 4.22(2H,q), 4.62(1H,d), 4.72(1H,d), 5.07(1H,s), 5.22(1H,d), 5.32(1H,d), 6.40(1H,s), 6.90-7.50(8H,m).

Reference Example 6

The method described as Reference Example 5 was repeated, while employing various aldehydes and ethyl isobutyryl acetates or ethyl acetoacetates. Compounds represented by chemical formula (6) thus obtained were collectively shown in the following Table 3.

                  TABLE 3                                                          ______________________________________                                          ##STR34##                                                                     Ref. Ex. 6                                                                             5-       6-       7-     Yield  m.p.                                   Cpd. No.                                                                               Substit. Substit. Substit.                                                                              (%)    (°C.)                           ______________________________________                                         1       phenyl   iso-     methyl 64     powder                                                  propoxy-                                                                       carbonyl                                                      2       4-cyclo- ethoxy-  iso-   32     "                                              hexyl-   carbonyl propyl                                                       phenyl                                                                 3       4-cyclo- ethoxy-  methyl 28     "                                              hexyl-   carbonyl                                                              phenyl                                                                 4       4-cyano- ethoxy-  "      42     "                                              phenyl   carbonyl                                                      ______________________________________                                    

Reference Example 7 Production of 5,8-dihydro-2,4-(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 7) ##STR35##

The compound (0.2 g, 0.35 mmol.) obtained in Reference Example 5 was dissolved in methanol (20 ml). To the solution was added a 2N aqueous solution of sodium hydroxide (2 ml), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, whose pH was adjusted to pH ranging from 2 to 3 with 1N HCl, followed by subjecting to extraction with ethyl acetate to give 0.13 g (yield 68%) of a yellow oily product.

Reference Example 8

Using compounds referred to in Reference Example 6, the method described in Reference Example 7 was repeated. The compounds represented by the chemical formula (8) thus obtained were collectively listed in the following Table 4.

                  TABLE 4                                                          ______________________________________                                          ##STR36##                                                                     Ref. Ex. 8                                                                             5-       6-       7-     Yield  m.p.                                   Cpd. No.                                                                               Substit. Substit. Substit.                                                                              (%)    (°C.)                           ______________________________________                                         1       phenyl   iso-     methyl 59     powder                                                  propoxy-                                                                       carbonyl                                                      2       4-cyclo- ethoxy-  iso-   57     "                                              hexyl-   carbonyl propyl                                                       phenyl                                                                 3       4-cyclo- ethoxy-  methyl 89     "                                              hexyl-   carbonyl                                                              phenyl                                                                 4       4-cyano- "        "      47     "                                              phenyl                                                                 ______________________________________                                    

Reference Example 9 Production of 2,4-(1H,3H)-dioxo-6-2-cyanoethoxycarbonyl)-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine (Chemical Formula 9) ##STR37##

The compound (3.9 g, 16 mmol.) obtained in Reference Example 2 was stirred in dimethylsufoxide (23 ml) for 25 mimutes at 125° C. together with the compound (6.1 g, 19 mmol) obtained by dehydrative condensation of quinoline-2-carboxyaldehyde and 2-cyanoethyl isobutyryl acetate. The reaction mixture was cooled, then poured into ice water. Resulting brownish crystals were collected by filtration and dissolved in ethyl acetate. Washing the solution with water, pale gray powder 4.3 g (yield 49%) was obtained. The compound thus obtained (4.3 g, 7.8 mmol) was dissolved in acetic acid (50 ml), to which was added sodium nitrite (5.9 g). The mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into ice water, which was subjected to extraction with ethyl acetate. The organic layer was dried and then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 4.1 g (yield 47%) of a yellow amorphous product. The elemental analysis values were shown in Table 5. The NMR spectrum and IR spectrum of the compound are as follows.

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 1.14(6H,d), 2.12(2H,t), 3.15(1H,m), 3.89(3H,s), 3.94(2H,t), 5.61(2H,s), 6.80-6.96(3H,m), 7.21(1H,td), 7.53(1H,d), 7.59(1H,td), 7.72(1H,td) 7.88(1H,d), 8.04(1H,d), 8.22(1H,d), 8.77(1H,s).

IR (KBr): 3452, 3196, 3068, 2974, 2254, 1736, 1715, 1603, 1572, 1497 cm⁻¹.

                  TABLE 5                                                          ______________________________________                                         Elemental Analysis for C.sub.31 H.sub.27 N.sub.5 O.sub.5.1.0H.sub.2 O                 C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   65.60         5.15    12.34                                           Found    65.59         5.05    12.11                                           ______________________________________                                    

Reference Example 10

Using another compounds, the method described in Reference Example 9 was repeated. The compounds represented by the chemical formula (10) thus obtained were collectively listed in the following Table 6.

                                      TABLE 6                                      __________________________________________________________________________      ##STR38##                                                                     Re. Ex. 10                                                                           1-substit.                                                                               5-substit. 6-substit.  7-substit.                                                                             Yield                                                                              m.p.                        Cpd. No.                                                                             (R.sup.1) (QR.sup.3) (R.sup.4)   (R.sup.5)                                                                              (%) (°C.)                __________________________________________________________________________     1     2-methoxy-benzyl                                                                         4-tolyl    2-cyanoethoxycarbonyl                                                                      isopropyl                                                                              42  powder                      2     "         4-methoxy-phenyl                                                                          "           "       19  "                           3     "         2-quinolyl "           methyl  44  "                           4     "         "          "           phenyl  46  "                           5     "         "          "           3,4-methylene-                                                                         32  "                                                                  dioxy-phenyl                            6     2,4-dimetboxybenzyl                                                                      "          "           isopropyl                                                                              83  "                           7     3-methoxy-benzyl                                                                         "          "           methyl  26  "                           8     2,4-dimethoxybenzyl                                                                      "          etboxycarbonyl                                                                             isopropyl                                                                              48  208-209                     9     2-methoxybenzyl                                                                          "          2-cyanoethoxycarbonyl                                                                      normalpropyl                                                                           56  powder                      10    "         "          "           isobutyl                                                                               55  105-107                     11    "         2-benzofuranyl                                                                            "           isopropyl                                                                              43  powder                      12    "         3-methylbenzothienyl                                                                      "           "       36  "                           13    "         2-quinolyl "           ethyl   72  "                           14    2-methoxyphenyl                                                                          "          "           isopropyl                                                                              34  "                           15    2-methoxybenzyl                                                                          3-quinolyl "           "       25  "                           __________________________________________________________________________

Reference Example 11 Production of Ethyl [2,4-(1H,3H)-dioxo-5-methylthio-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 11) ##STR39##

To a methanol solution (5 ml) containing ethylisobutylylacetate (0.48 g) was added a methanol solution of sodiumu methoxide (28%, 0.58 g) under ice cooling. After stirring for 10 minutes under same condition, to the solution was added dropwise carbon disulfide. After completion of the dropwise addition, dimethyl sulfate (0.75 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water (30 ml), stirred for 5 minutes, which was then subjected to extraction with isopropyl ether to give a yellow oily product (0.40 g).

A mixture of the the oily product, the compound obtained in Reference Example 4 (0.50 g, 1.5 mmol) and potassium carbonate (0.31 g) was stirred in dimethylformamide (10 ml) for 5 hours at 150° C. The reaction mixture was, after cooling, concentrated to dryness, to which were added a saturated aqueous solution of ammonium chloride (20 ml) and ethyl acetate (20 ml), and then the mixture was stirred. The organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate (20 ml). The extract was combined with the organic layer, which was then dried. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.06 g (yield 8%) of a yellow amorphous product. The NMR spectrum and MS spectrum of thus obtained yellow amorphous compound was as follows.

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 1.28(3H,t), 1.35(6H,d), 1.41(3H,t), 2.21(3H,s), 3.86(3H,s), 4.20(2H,q), 4.40(2H,q), 4.40-4.60(1H,m), 4.84(2H,s), 5.59(2H,s), 6.7-7.0(3H,m), 7.15-7.3(1H,m).

MS, m/z: 530(MH)⁺

Reference Example 12 Production of Ethyl [1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6-isopropyl-pyrimido[4",5":6',5']pyrido[3',4':4,3]pyrrolo[1,2-a]quinoline]-3-acetate (Chemical Formula 12) ##STR40##

The compound (1.10 g, 2.38 mmol.) obtained in Example 17 (Compound No. 16) was dissolved in dichloromethane (100 ml). To the solution was added thionyl chloride (0.87 ml, 11.89 mmol), and the mixture was stirred for 2 hours at room temperature. 20 ml of toluene was added to the reaction mixture, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then filtered with sellaite. The filtrate was concentrated, and the residue thus obtained was washed with ethyl acetate to give 0.30 g (yield 28%) of a yellow powdery product. The elemental analysis values were shown in Table 7. The NMR spectrum, IR spectrum and MS spectrum of the compound are as follows.

¹ H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.32-1.41(9H,m), 4.28(2H,q), 4.37(1H,m), 4.82(2H,s), 7.47(1H,t), 7.78(1H,t), 8.30(1H,d), 8.64(1H,s), 8.78(1H,s), 9.19(1H,d)

IR (KBr): 1738, 1682, 1642, 1576, 1477, 1396 cm⁻¹.

FAB-MS, m/z: 461.1(MH)⁺

                  TABLE 7                                                          ______________________________________                                         Elemental Analysis for C.sub.24 H.sub.20 N.sub.4 O.sub.6 :0.3H.sub.2           O:0.2C.sub.4 H.sub.8 O.sub.2                                                          C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   61.62         4.62    11.58                                           Found    61.41         4.32    11.40                                           ______________________________________                                    

Reference Example 13 Production of Ethyl [1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6-isopropyl-4-(2-methylthiobenzyl)pyrimido[4",5":6',5']pyrido[3',4':4,3]pyrrolo[1,2-a]quinoline]-3-acetate (Chemical Formula 13) ##STR41##

A dimethylformamide (5 ml) solution containing the compound (0.20 g, 0.43 mmol.) obtained in Reference Example 12, 2-methylthio benzylchloride (0.74 g, 4.30 mmol) and potassium hydrogen carbonate (0.07 g, 0.64 mmol) was stirred for 2 days at room temperature. To the reaction mixture was added and a saturated aqueous solution of ammonium chloride, which was subjected to distribution to dichloromethane and a saturated aqueous solution of sodium chloride. The organic layer was dried with MgSO₄ and then the solvent was distilled off under reduced pressure.

The residue was purified by means of a silica gel column chromatography to give 0.21 g (yield 80%) of a yellow powdery product.

The elemental analysis values were shown in Table 8. The NMR spectrum, IR spectrum and MS spectrum of the compound are as follows.

¹ H-NMR (200 MHz, CDCl₃)δ ppm: 1.14(6H,d), 1.34(3H,t), 2.57(3H,s), 4.23-4.34(3H,m), 4.93(2H,s), 5.76(2H,s), 6.83(1H,d), 7.03(1H,t), 7.22-7.35(2H,m), 7.47(1H,t), 7.77(1H,t), 8.32(1H,d), 8.84(1H,s), 9.18(1H,d).

IR (KBr): 1725, 1680, 1640, 1578, 1475 cm⁻¹.

FAB-MS, m/z: 597.1(MH)⁺

                  TABLE 8                                                          ______________________________________                                         Elemental Analysis for C.sub.12 H.sub.28 N.sub.4 O.sub.8 S.0.8H.sub.2 O               C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   62.89         4.88    9.16                                            Found    63.14         4.67    8.88                                            ______________________________________                                    

Reference Example 14

Using compounds referred to in Reference Example 12, the method described in Reference Example 13 was repeated. The compounds represented by the chemical formula (14), thus obtained, were collectively listed in the following Table 9.

                  TABLE 9                                                          ______________________________________                                          ##STR42##                                                                     Ref. Ex. 14                                                                            1-substit.  7-substit.                                                                               Yield  m.p.                                      Cpd. No.                                                                               (R.sup.1)   (R.sup.5) (%)    (°C.)                              ______________________________________                                         1       2,3-dimethoxy-                                                                             isopropyl 71     258-259                                           benzyl                                                                 2       2,3,4-tri-  isopropyl 72     209-210                                           methoxybenzyl                                                          ______________________________________                                    

Example 1 Production of Ethyl [2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 15) ##STR43##

The compound (2.1 g, 6.3 mmol.) obtained in Reference Example 4 was heated for 130 hours under reflux in ethanol (40 ml) together with p-anisaldehyde (0.81 g, 6.0 mmol.) and ethyl acetoacetate (0.79 g, 6.1 mmol.). The reaction mixture was cooled, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 2.6 g (yield 70%) of a yellow amorphous product. The amorphous compound (2.3 g, 4.1 mmol.) was dissolved in acetic acid (50 ml), to which was added sodium nitrite (2.0 g). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate (100 ml each, twice). The organic layer was dried, and then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 1.8 g (yield 77%) of a yellow oily product. The NMR spectrum of this product was as follows.

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.97(3H,t), 1.22(3H,t), 2.51(3H,s), 3.84(3H,s), 3.90(3H,s), 3.98(2H,q), 4.15(2H,q), 4.71(2H,s), 5.65(2H, s), 6.75-7.61(8H,m).

Example 2

Using suitable aldehyde instead of p-anisaldehyde and ethyl isobutyryl acetate or ethyl acetoacetate, the method described in Example 1 was repeated to give corresponding compounds of chemical formula 16, which were listed in Table 10.

                  TABLE 10                                                         ______________________________________                                          ##STR44##                                                                     Ex. 2  5-        6-       7-     Yield  m.p.                                   Cpd. No.                                                                              substit.  substit. substit.                                                                              (%)    (°C.)                           ______________________________________                                          1     2-methoxy-                                                                               ethoxy-  methyl 44     powder                                        phenyl    carbonyl                                                       2     2-tolyl   ethoxy-  "      76     "                                                       carbonyl                                                       3     2-bromo-  ethoxy-  "      48     "                                             phenyl    carbonyl                                                       4     2-nitro-  ethoxy-  "      59     "                                             phenyl    carbonyl                                                       5     3-methoxy-                                                                               ethoxy-  "      67     "                                             phenyl    carbonyl                                                       6     3-tolyl   ethoxy-  "      43     "                                                       carbonyl                                                       7     3-bromo-  ethoxy-  "      58     "                                             phenyl    carbonyl                                                       8     3-nitro-  ethoxy-  "      35     "                                             phenyl    carbonyl                                                       9     3-cyano-  ethoxy-  "      55     "                                             phenyl    carbonyl                                                      10     4-tolyl   ethoxy-  "      73     "                                                       carbonyl                                                      11     4-bromo-  ethoxy-  "      55     "                                             phenyl    carbonyl                                                      12     4-nitro-  ethoxy-  "      73     "                                             phenyl    carbonyl                                                      13     4-biphenyl                                                                               ethoxy-  "      61     "                                                       carbonyl                                                      14     1-naphthyl                                                                               ethoxy-  "      43     "                                                       carbonyl                                                      15     2-naphthyl                                                                               ethoxy-  "      22     "                                                       carbonyl                                                      16     4-pyridyl ethoxy-  "      68     "                                                       carbonyl                                                      17     3-pyridyl ethoxy-  "      69     "                                                       carbonyl                                                      18     2-pyridyl ethoxy-  "      28     "                                                       carbonyl                                                      19     6-methyl- ethoxy-  "      38     "                                             2-pyridyl carbonyl                                                      20     3-        ethoxy-  "      34     "                                             quinolinyl                                                                               carbonyl                                                      21     4-        ethoxy-  "      58     "                                             quinolinyl                                                                               carbonyl                                                      22     2-thienyl ethoxy-  "      50     "                                                       carbonyl                                                      23     3-thienyl ethoxy-  "      44     "                                                       carbonyl                                                      24     3-methyl- ethoxy-  "      44     "                                             2-thienyl carbonyl                                                      25     5-methyl- ethoxy-  "      63     "                                             2-thienyl carbonyl                                                      26     3-qunolyl ethoxy-  iso-   33     "                                                       carbonyl propyl                                               27     3,4-dimeth                                                                               ethoxy-  "      47     "                                             oxyphenyl carbonyl                                                      28     4-methoxy-                                                                               ethoxy-  iso-   12     "                                             phenyl    carbonyl propyl                                               29     4-methoxy ethoxy-  phenyl 27     "                                             phenyl    carbonyl                                                      30     "         cyclopen iso-   58     "                                             4-methoxy tyloxyca butyl                                                       phenyl    rbonyl                                                        31     3,4-dimeth                                                                               ethoxy-  iso-   37     "                                             oxyphenyl carbonyl propyl                                               32     3,3-methyl                                                                               ethoxy-  iso-   52     "                                             enedioxyph                                                                               carbonyl propyl                                                      enyl                                                                    ______________________________________                                    

Example 3 Production of t-Butyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 17) ##STR45##

The compound (1.0 g, 1.9 mmol.) obtained in Reference Example 9 was stirred for 40 minutes at room temperature in dimethylformamide (5 ml) together with tert-butyl bromoacetate (0.88 ml, 5.6 mmol) and potassium carbonate (0.76 g, 5.6 mmol). The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.51 g (yield 41%) of a yellow amorphous product. The elemental analysis values of the compound thus obtained were shown in Table 11. The NMR spectrum and IR spectrum of the compound are as follows.

                  TABLE 11                                                         ______________________________________                                         Elemental Analysis for C.sub.37 H.sub.37 N.sub.5 O.sub.7                              C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   66.96         5.62    10.55                                           Found    66.77         5.74    10.51                                           ______________________________________                                    

¹ -NMR (200 MHz, CDCl₃) δ ppm: 1.15(6H,d), 1.40(9H,s), 2.14(2H,t), 3.15(1H,m), 3.90(2H,s), 3.94(2H,t), 4.59(2H,s), 5.69(2H,s), 7.22(1H,td), 7.54(1H,d), 7.60(1H,td) 7.73(1H,td), 7.88(1H,d), 8.04(1H,d), 8.22(1H,d).

IR (KBr): 3452, 2976, 2938, 2364, 2258, 1742, 1721, 1678, 1603, 1574 cm⁻¹.

Example 4

Using the corresponding compound for starting material, the method described in Example 3 was repeated to give compounds of chemical formula 18, which were listed in Table 12.

                                      TABLE 12                                     __________________________________________________________________________      ##STR46##                                                                     Ex. 4                                                                               1-substit.     5-substit.                                                                              6-substit.                                                                             7-substit.                                                                             Yield                                                                               m.p.                         Cpd. No.                                                                            (R.sup.1)                                                                               n R.sup.2                                                                            (QR.sup.3)                                                                              (R.sup.4)                                                                              (R.sup.5)                                                                              (%)  (°C.)                 __________________________________________________________________________      1   2-methoxy-benzyl                                                                        1 t-butyl                                                                            4-tolyl  2-cyanoethoxy-                                                                         iso-propyl                                                                             64   powder                        2   "        1 ethyl                                                                              4-methoxy-phenyl                                                                        "       "       74   "                             3   "        3 "   "        "       "       48   "                             4   "        1 t-butyl                                                                            2-quinolyl                                                                              "       methyl  87   "                             5   "        1 ethyl                                                                              "        "       iso-propyl                                                                             86   "                             6   "        3 "   "        "       "       43   "                             7   "        1 t-butyl                                                                            "        "       phenyl  53   "                             8   "        1 "   "        "       3,4-methylene-                                                                         86   "                                                                 dioxyphenyl                                9   "        1 ethyl                                                                              "        "       methyl  69   "                            10   2,4-dimethoxy-                                                                          1 "   "        "       iso-propyl                                                                             70   "                                 benzyl                                                                    11   2,4-dimethoxy-                                                                          1 t-butyl                                                                            "        "       "       78   "                                 benzyl                                                                    12   "        1 ethyl                                                                              "        ethoxycarbonyl                                                                         "       73   "                            13   2-methoxy-benzyl                                                                        1 "   "        2-cyanoethoxy-                                                                         normal- 74   "                                                         carbonyl                                                                               propyl                                    14   "        1 "   "        2-cyanoethoxy-                                                                         iso-butyl                                                                              77   164-165                                                   carbonyl                                          15   "        1 "   2-benzofuranyl                                                                          2-cyanoethoxy-                                                                         iso-propyl                                                                             77   powder                                                    carbonyl                                          16   "        1 "   3-methyl-2-                                                                             2-cyanoethoxy-                                                                         "       84   "                                                benzothienyl                                                                            carbonyl                                          17   "        1 "   2-quinolyl                                                                              2-cyanoethoxy-                                                                         ethyl   86   "                                                         carbonyl                                          18   2-methoxy-phenyl                                                                        1 t-butyl                                                                            "        2-cyanoethoxy-                                                                         iso-propyl                                                                             89   "                                                         carbonyl                                          19   2-methoxy-benzyl                                                                        1 ethyl                                                                              "        2-cyanoethoxy-                                                                         "       79   "                                                         carbonyl                                          __________________________________________________________________________

Example 5 Production of Ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 19) ##STR47##

The compound (Compound No. 10; 10.0 g, 15.0 mmol.) obtained in Example 4 was dissolved in aceton-water (1:1 v/v, 600 ml). To the solution was added cerium(IV)ammonium nitrate (24.7 g, 45.0 mmol), and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated into 1/2 volume, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried (with Na₂ SO₄), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 4.59 g (yield 46%) of yellow powdery products. The elemental analysis values were shown In Table 13. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

                  TABLE 13                                                         ______________________________________                                         Elemental Analysis for C.sub.27 H.sub.25 N.sub.5 O.sub.6.0.5H.sub.2 O                 C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   61.82         4.99    13.35                                           Found    61.88         5.23    12.64                                           ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 1.21(3H, t), 1.35(6H,d), 2.17(2H,t), 3.25(1H,m), 3.97(2H,t), 4.15(2H,q), 4.61(2H,s), 7.53(1H,d), 7.61(1H,t), 7.74(1H,t), 7.89(1H,d), 8.05(1H,d), 8.23(1H,d), 8.56(1H,s).

IR (KBr): 3424, 3264, 2976, 2362, 1734, 1680, 1620, 1578, 1504 cm⁻¹.

Example 6 Production of Ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 20) ##STR48##

The solution of the compound (Compound No.10; 9.1 g, 13.7 mmol.) obtained in Example 4 in trifluoroacetic acid (50 ml) was stirred for 4 hours at 60° C. The reaction mixture was concentrated to remove trifluoroacetic acid, and the residue was subjected to distribution in ethyl acetate-aqueous solution of sodium chloride. The organic layer was dried (with MgSO₄), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 6.47 g (yield 92%) of yellow powdery products.

Example 7

Using the compound obtained in Example 4 (Compound No. 12), the method described in Example 5 was repeated to give the compound represented by the Chemical Formula 21). ##STR49##

Example 8 Production of Ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropy-1-methyl-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 22) ##STR50##

The compound (1.78 g, 3.5 mmol.) obtained in Example 5, methyl iodide (0.98 g, 6.9 mmol) and pottasium crbonate (1.42 g, 10.4 mmol) were dissolved in dimethylformamide (70 ml). To the solution was added 1N HCl, and was subjected to distribution in ethyl acetate-water. The organic layer was dried (with Na₂ SO₄), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 1.42 g (yield 78%) of yellow bubbly products. The elemental analysis values were shown in Table 14. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

                  TABLE 14                                                         ______________________________________                                         Elemental Analysis for C.sub.28 H.sub.27 N.sub.5 O.sub.6.0.1H.sub.2 O                 C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   63.12         5.10    13.23                                           Found    63.29         5.15    13.18                                           ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 1.21(3H,t), 1.39(6H,d), 2.14(1H,t), 3.30(1H,m), 3.82(3H,s), 3.96(2H,t), 4.15(2H,q), 4.65 (2H,s), 7.50(1H,d), 7.59(1H,t), 7.73(1H,t), 7.88(1H,d), 8.03(1H,d), 8.21(1H,d).

IR (KBr): 3452, 2974, 2364, 1742, 1719, 1673, 1620, 1601, 1574, 1506 cm⁻¹.

Example 9

Using the corresponding compounds as starting material, the method described in Example 8 was repeated to give the compound represented by the Cemical Formula (23), which has various 1-position substituents. Compounds thus obtained were collectively shown In the following Table 15.

                  TABLE 15                                                         ______________________________________                                          ##STR51##                                                                     Ex. 9     1-substituent  Yield    m.p.                                         Cpd. No.  (R.sup.1)      (%)      (°C.)                                 ______________________________________                                         1         2-quinolylmethyl                                                                              97       powder                                       2         2-methoxyphenetyl                                                                             92       "                                            3         3-indolylethyl 62       "                                            ______________________________________                                    

Example 10 Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxbenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 24) ##STR52##

The compound (0.13 g, 0.24 mmol.) obtained in Reference Example 7 was dissolved in acetic acid (20 ml). To the solution was added sodium nitrite (0.1 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate (20 ml each, three times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography. Crude crystals thus obtained were recrystallized from ethyl acetate-isopropyl ether (1:2) to give 0.06 g (yield 54%) of yellow powdery crystals, m.p.190°-192° C. (decomp.). The elemental analysis values were shown in Table 16. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

                  TABLE 16                                                         ______________________________________                                         Elemental Analysis for C.sub.30 H.sub.31 N.sub.3 O.sub.7.2H.sub.2 O                   C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   61.95         6.07    7.22                                            Found    61.77         5.80    7.12                                            ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.89(3H, t), 1.08(6H,d), 2.25(3H,s), 2.9-3.1(1H,m), 3.41(3H,s), 3.90(2H,q), 4.41(2H,s), 5.53(2H,s), 6.6-7.2(8H,m).

IR (KBr): 3456, 1717, 1671, 1562, 1518, 1495, 1466, 1386, 1371, 1305, 1247 cm⁻¹.

Example 11

Using compounds reffered to in Reference Example 8, the method described in Example 10 was repeated. The compounds thus obtained (Chemical Formula 25) were listed in Table 17.

                  TABLE 17                                                         ______________________________________                                          ##STR53##                                                                            5-       6-       7-                                                    Ex. 11 substit. substit. substit.                                                                              Yield  m.p.                                    Cpd. No.                                                                              (QR.sup.3)                                                                              (R.sup.4)                                                                               (R.sup.5)                                                                             (%)    (°C.)                            ______________________________________                                         1      phenyl   iso-     methyl 50     215-220                                                 propoxy-                                                                       carbonyl                                                       2      4-cyclo- ethoxy-  iso-   55     powder                                         hexyl-   carbonyl propyl                                                       phenyl                                                                  3      4-cyclo- ethoxy-  methyl 38     "                                              hexyl-   carbonyl                                                              phenyl                                                                  4      4-cyano- ethoxy-  "      46     155-158                                        phenyl   carbonyl                                                       ______________________________________                                    

Example 12 Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 26) ##STR54##

The compound (Compound No. 10: 1.5 g, 2.6 mmol.) obtained in Example 2 was dissolved in methanol (30 ml), to which was added a 2N aqueous solution of sodium hydroxide (2.6 ml), and the mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH ranging from 2 to 3 with 1N HCl, which was subjected to extraction with ethyl acetate. The extract was purified by means of a silica gel column chromatography to give crude crystals, followed by recrystallization from isopropyl alcohol to give 0.63 g (yield 46%) of yellow powdery crystals, m.p. 190°-192° C. Elemental analysis of the product is shown in Table 18. The NMR spectrum and IR spectrum of the compound were as follows.

                  TABLE 18                                                         ______________________________________                                         Elemental Analysis for C.sub.28 H.sub.27 N.sub.3 O.sub.6.2.25H.sub.2 O                C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   58.58         5.53    7.32                                            Found    58.73         5.22    7.31                                            ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.88(3H,t), 2.39(3H,s), 3.79(3H,s), 3.89(3H,s), 3.92(2H,q), 4.18(2H,s), 5.47(2H,s), 6.78(1H,t), 6.68(1H,d), 6.91(2H,d), 7.01(1H,d), 7.06(2H,d), 7.20(1H,t).

IR (KBr): 3450, 1717, 1669, 1609, 1564, 1518, 1483, 1381, 1278, 1247 cm⁻¹.

Example 13

Using compounds reffered to in Example 2 (except Compound No. 19), Example 7 and Example 9, the method described in Example 12 was repeated. Compounds thus obtained (Chemical Formula 27) are listed in Table 19.

                  TABLE 19                                                         ______________________________________                                          ##STR55##                                                                            1-        5-        7-                                                  Ex. 13 substit.  substit.  substit.                                                                             Yield  m.p.                                   Cpd. No.                                                                              (R.sup.1) (QR.sup.3)                                                                               (R.sup.5)                                                                            (%)    (°C.)                           ______________________________________                                         1      2-methoxy-                                                                               2-methoxy-                                                                               methyl                                                                               44     powder                                        benzyl    phenyl                                                        2      2-methoxy-                                                                               2-tolyl   "     45     "                                             benzyl                                                                  3      2-methoxy-                                                                               2-bromo-  "     65     214-216                                       benzyl    phenyl                                                        4      2-methoxy-                                                                               2-nitro-  "     44     212-214                                       benzyl    phenyl                                                        5      2-methoxy-                                                                               3-methoxy-                                                                               "     51     192-194                                       benzyl    phenyl                                                        6      2-methoxy-                                                                               3-tolyl   "     54     powder                                        benzyl                                                                  7      2-methoxy-                                                                               3-bromo-  "     51     214-216                                       benzyl    phenyl                                                        8      2-methoxy-                                                                               3-nitro-  "     66     224-226                                       benzyl    phenyl                                                        9      2-methoxy-                                                                               3-cyano-  "     61     226-228                                       benzyl    phenyl                                                        10     2-methoxy-                                                                               4-methoxy-                                                                               "     46     powder                                        benzyl    phenyl                                                        11     2-methoxy-                                                                               4-tolyl   "     35     204-206                                       benzyl                                                                  12     2-methoxy-                                                                               4-bromo-  "     62     208-210                                       benzyl    phenyl                                                        13     2-methoxy-                                                                               4-nitro-  "     55     powder                                        benzyl    phenyl                                                        14     2-methoxy-                                                                               4-biphenyl                                                                               "     63     "                                             benzyl                                                                  15     2-methoxy-                                                                               1-naphthyl                                                                               "     36     206-208                                       benzyl                                                                  16     2-methoxy-                                                                               2-naphthyl                                                                               "     89     powder                                        benzyl                                                                  17     2-methoxy-                                                                               4-pyridyl "     64     "                                             benzyl                                                                  18     2-methoxy-                                                                               3-pyridyl "     53     "                                             benzyl                                                                  19     2-methoxy-                                                                               6-methyl- "     93     "                                             benzyl    2-pyridyl                                                     20     2-methoxy-                                                                               3-quinolyl                                                                               "     79     "                                             benzyl                                                                  21     2-methoxy-                                                                               4-quinolyl                                                                               "     66     "                                             benzyl                                                                  22     2-methoxy-                                                                               2-thienyl "     53     202-204                                       benzyl                                                                  23     2-methoxy-                                                                               3-thienyl "     53     powder                                        benzyl                                                                  24     2-methoxy-                                                                               3-methyl- "     48     "                                             benzyl    2-thienyl                                                     25     2-methoxy-                                                                               5-methyl- "     71     "                                             benzyl    2-thienyl                                                     26     hydrogen  2-quinolyl                                                                               iso-  55     135-137                                       atom                propyl                                              27     2-quinol  "         iso-  57     >300                                          ylmethyl            propyl                                              28     2-methoxy "         iso-  100    163-164                                       phenyl              propyl                                              29     3-indol-  "         iso-  73     210-212                                       ethyl               propyl                                              ______________________________________                                    

Example 14 Production of 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 28) ##STR56##

The compound (Compound No. 5: 0.20 g, 0.31 mmol.) obtained in Example 4 was dissolved in the mixture of methanol (1.0 ml) and 1,4-dioxane (2.0 ml) to which was added a 1N aqueous solution of sodium hydroxide (0.63 ml, 1.3 mmol), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropyl ether to give 0.12 g (yield 71%) of pale yellow powdery crystals, m.p. over 300° C. Elemental analysis of the product is shown in Table 20. The NMR spectrum and IR spectrum of the compound were as follows.

                  TABLE 20                                                         ______________________________________                                         Elemental Analysis for C.sub.30 H.sub.26 N.sub.4 O.sub.7.0.75H.sub.2 O                C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   63.43         4.88    9.86                                            Found    63.45         4.66    9.73                                            ______________________________________                                    

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 1.05(6H,d), 3.19(1H,m), 3.90(3H,s), 4.47(2H,s), 5.55(2H,s), 6.83(1H,t), 6.93(1H,d), 7.05(1H,d), 7.24(1H,dd), 7.52(1H,d), 7.65(1H,dd), 7.77(1H,dd), 7.93(1H,d), 8.02(1H,dd), 8.32(1H,d), 12.97(2H,br).

IR (KBr): 3480, 2980, 1715, 1671, 1576, 1493, 1464 cm⁻¹.

Example 15

Using compounds reffered to in Example 4, the method described in Example 14 was repeated. Compounds thus obtained (Chemical Formula 29) are listed in Table 21.

                  TABLE 21                                                         ______________________________________                                          ##STR57##                                                                     Ex. 15 1-substit.       5-substit.                                                                              Yield  m.p.                                   Cpd. No.                                                                              (R.sup.1) n      (QR.sup.3)                                                                              (%)    (°C.)                           ______________________________________                                         1      2-methoxy-                                                                               1      4-tolyl  53     245-247                                       benzyl                                                                  2      2-methoxy-                                                                               1      4-methoxy-                                                                              71     123-125                                       benzyl           phenyl                                                 3      2-methoxy-                                                                               3      4-methoxy-                                                                              84     150-152                                       benzyl           phenyl                                                 4      2,4-di-meth-                                                                             1      2-quinolyl                                                                              61     274-282                                       oxy-benzyl                                                              5      2-methoxy-                                                                               1      "        84     292-293                                       phenethyl                                                               6      methyl    1      "        75     259-260                                7      2-methoxy-                                                                               1      2-benzo- 90     248-249                                       benzyl           furanyl                                                8      2-methoxy-                                                                               1      3-methyl-2-                                                                             85     144-145                                       benzyl           benzothienyl                                           9      2-methoxy-                                                                               1      3-quinolyl                                                                              61     203-204                                       benzyl                                                                  ______________________________________                                    

Example 16

Production of t-Butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 30) ##STR58##

The compound (2.9 g, 4.3 mmol.) obtained in Example 3 was dissolved in the mixture of methanol (130 ml) and water (17 ml), to which was added a 2N aqueous solution of potassium carbonate (8.6 ml, 8.6 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was adjusted to pH ranging from 2 to 3 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was was purified by means of a silica gel column chromatography to give 2.3 g (yield 87%) of yellow powdery crystals, m.p. over 300° C. Elemental analysis of the product is shown in Table 22. The NMR spectrum and IR spectrum of the compound were as follows.

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 1.05(6H,d), 1.34(9H,s), 3.19(1H,m), 3.90(3H,s), 4.45(2H,s), 5.54(2H,s), 6.83-6.92(2H,m), 7.06(1H,d), 7.24(1H,td), 7.53(1H,d), 7.65(1H,t), 7.77(1H,t), 7.94(1H,d), 8.04(1H,d), 8.33(1H,d).

IR (KBr): 3454, 2972, 2928, 2366, 1719, 1678, 1605, 1572, 1495 cm⁻¹.

                  TABLE 22                                                         ______________________________________                                         Elemental Analysis for C.sub.34 H.sub.34 N.sub.4 O.sub.7.0.25H.sub.2 O                C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   66.38         5.65    9.11                                            Found    66.30         5.61    8.92                                            ______________________________________                                    

Example 17

Using compounds reffered to in Example 4 and others, the method described in Example 16 was repeated. Compounds thus obtained (Chemicl Formula 31) are listed in Table 23.

                                      TABLE 23                                     __________________________________________________________________________      ##STR59##                                                                     Ex. 17                                                                              1-substit.      5-substit. 7-substit.                                                                             Yield                                                                               m.p.                              Cpd. No.                                                                            (R.sup.1) n R.sup.2                                                                            (QR.sup.3) (R.sup.5)                                                                              (%)  (°C.)                      __________________________________________________________________________     1    2-methoxy-benzyl                                                                         1 ethyl                                                                              2-quinolyl isopropyl                                                                              88   230-231                           2    "         3 "   "          "       48   158-159                           3    "         1 t-butyl                                                                            "          methyl  77   >300                              4    "         1 "   "          phenyl  73   175-177                           5    "         1 "   "          3,4-methylene-                                                                         98   >300                                                              dioxy-phenyl                                   6    2,4-dimethoxybenzyl                                                                      1 ethyl                                                                              "          isopropyl                                                                              69   184-186                           7    methyl    1 "   "          "       72   219-221                           8    2-methoxyphenethyl                                                                       1 "   "          "       87   219-220                           9    2-methoxybenzyl                                                                          1 "   "          normalpropyl                                                                           84   163-165                           10   "         1 "   "          isobutyl                                                                               94   218-220                           11   "         1 "   2-benzofuranyl                                                                            isopropyl                                                                              88   225-226                           12   "         1 "   3-methylbenzothienyl                                                                      "       93   powder                            13   "         1 "   2-quinolyl ethyl   96   "                                 14   2-methoxyphenyl                                                                          1 t-butyl                                                                            "          isopropyl                                                                              67   >300                              15   2-methoxybenzyl                                                                          1 ethyl                                                                              3-quinolyl "       95   powder                            16   hydrogen atom                                                                            1 "   2-quinolyl "       90   >300                              __________________________________________________________________________

Example 18 Production of t-Butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 32) ##STR60##

The compound (500 mg, 0.82 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0.60 ml, 8.20 mmol), and the mixture was heated for 30 minutes under reflux. The reaction mixture was cooled and concentrated. The residue was dissolved in dimethylacetamide (40 ml) and stirred with 2N aqueous solution of potassium carbonate for 22 hours at 90° C. After cooling, the reaction mixture was poured into ice-water and was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to extraction with ethyl acetate (150 ml). The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 190 mg (yield 37%) of pale brown powder. The powder thus obtained were recrystallized from mixed solvent of iso-propanol and isopropyl ether to give 40 mg (yield 8%) of pale brown powdery crystals, m.p. more than 300° C. The elemental analysis values were shown in Table 24. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 0.97(3H,d), 1.07(3H,d), 1.33(9H,s), 3.46(1H,m), 3.90(3H,s), 4.48(2H,s), 5.52(2H,q), 5.92(1H,s), 6.80(2H,s), 7.04(1H,d), 7.22(1H,td), 7.28(1H,t), 7.44(1H,d), 7.58(1H,td), 8.10(1H,d), 11.81(1H,s).

IR (KBr): 3452, 2974, 1717, 1673, 1638, 1601, 1570, 1510, 1473, cm⁻¹.

                  TABLE 24                                                         ______________________________________                                         Elemental Analysis for C.sub.34 H.sub.34 N.sub.4 O.sub.7.3.0HCl.2.0H.sub.2      O                                                                                    C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   52.89         5.35    7.26                                            Found    52.71         5.16    7.22                                            ______________________________________                                    

Example 19

Using compounds reffered to in Example 17 and others, the method described in Example 18 was repeated. Compounds thus obtained (Chemicl Formula 33) are listed in Table 25.

                  TABLE 25                                                         ______________________________________                                          ##STR61##                                                                     Ex. 19                       7-subs                                            Cpd.  1-substit.             tit.  Yield  m.p.                                 No.   (R.sup.1) n      (R.sup.2)                                                                            (R.sup.5)                                                                            (%)    (°C.)                         ______________________________________                                         1     2-methoxy-                                                                               1      T-butyl                                                                              methyl                                                                               33     >300                                       benzylyl                                                                 2     2-methoxy-                                                                               1      ethyl iso-  72     >300                                       benzylyl               propyl                                            3     2-methoxy-                                                                               3      "     iso-  25     264-266                                    benzylyl               propyl                                            4     2-methoxy-                                                                               1      t-butyl                                                                              phenyl                                                                               51     >300                                       benzylyl                                                                 5     2,4-dimeth                                                                               1      ethyl iso-  14     >300                                       oxybenzyl              propyl                                            6     2,4-dimeth                                                                               1      t-butyl                                                                              iso-  20     228-230                                    oxybenzyl              propyl                                            7     methyl    1      ethyl iso-  81     259-261                                                           propyl                                            8     3-methoxy-                                                                               1      "     methyl                                                                               56     280-283                                    benzyl                                                                   9     2-methoxy-                                                                               1      t-butyl                                                                              3,4-me                                                                               50     >300                                       benzyl                 thylen                                                                         edioxy                                                                         phenyl                                            10    2-methoxy-                                                                               1      ethyl normal                                                                               41     149-150                                    benzyl                 propyl                                            11    2-methoxy-                                                                               1      "     iso-  63     283-285                                    benzyl                 butyl                                             12    2-methoxy-                                                                               1      "     ethyl 19     >300                                       benzyl                                                                   13    2-methoxy-                                                                               1      "     iso-  60     >300                                       phenyl                 propyl                                            ______________________________________                                    

Example 20 Production of 2,4(1H,3H)-dioxo-6-carboxy -7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 34) ##STR62##

The compound (Compound No. 2: 0.19 g, 0.32 mmol.) obtained in Example 19 was dissolved in the mixture of methanol (2.0 ml) and tetrahydrofuran (2.0 ml), to which was added a 1N aqueous solution of sodium hydroxide (0.64 ml, 1.3 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to extraction with mixed solvent of ethyl acetate and tetrahydrofuran.

The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of methanol and isopropyl ether to give 0.08 g (yield 44%) of colorless powdery crystals, m.p. over 300° C. Elemental analysis of the product is shown in Table 26. The NMR spectrum and IR spectrum of the compound were as follows.

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 1.01(3H,d), 1.13(3H,d), 3.18(1H,m), 3.90(3H,s), 4.55(2H,q), 5.53(2H,q), 5.92(1H,s), 6.81-6.94(2H,m), 7.04(1H,d), 7.24(1H,t), 7.35(1H,t), 7.47(1H,d), 7.65(1H,t), 8.12(1H,d), 11.90(1H,s), 13.0(1H,brs).

IR (KBr): 3444, 2974, 1719, 1676, 1574, 1493 cm⁻¹.

                  TABLE 26                                                         ______________________________________                                         Elemental Analysis for C.sub.30 H.sub.26 N.sub.4 O.sub.7.0.5H.sub.2 O                 C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   62.17         4.70    9.67                                            Found    62.13         4.70    9.41                                            ______________________________________                                    

Example 21

Using compounds reffered to in Example 19 and others, the method described in Example 20 was repeated. Compounds thus obtained (Chemicl Formula 35) are listed in Table 27.

                  TABLE 27                                                         ______________________________________                                          ##STR63##                                                                     Ex. 21 1-substit.  7-substit. Yield  m.p.                                      Cpd. No.                                                                              (R.sup.1)   (R.sup.5)  (%)    (°C.)                              ______________________________________                                         1      2-methoxy-  methyl     65     >300                                             benzyl                                                                  2      2-methoxy-  phenyl     58     >300                                             benzyl                                                                  3      2-methoxy-  methyl     70     >300                                             benzyl                                                                  4      methyl      iso-propyl 57     >300                                      5      2,4-dimethoxy-                                                                             "          100    274-276                                          benzyl                                                                  6      2-methoxy-  normal     73     >300                                             benzyl      propyl                                                      7      2-methoxy-  iso-butyl  90     >300                                             benzyl                                                                  8      2-methoxy-  ethyl      50     >300                                             benzyl                                                                  9      2-methylthio-                                                                              iso-propyl 53     >300                                             benzyl                                                                  10     2,3-dimethoxy-                                                                             "          75     >300                                             benzyl                                                                  11     2,3,4-tri-  "          73     >300                                             methoxybenzyl                                                           ______________________________________                                    

Example 22 Production of t-Butyl [2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 36) ##STR64##

The compound (0.35 g, 0.56 mmol.) obtained in Example 18 was stirred with ethyl iodide (0.10 g, 0.91 mmol) in dimethylformamide (5.0 ml) for one hour at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, and was subjected to distribution in ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.18 g (yield 49%) of a pale brown amorphous product. The elemental analysis values of the compound thus obtained were shown in Table 28. The NMR spectrum and IR spectrum of the compound are as follows.

                  TABLE 28                                                         ______________________________________                                         Elemental Analysis for C.sub.36 H.sub.38 N.sub.4 O.sub.6.0.75H.sub.2 O                C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   64.71         5.96    8.38                                            Found    64.63         5.71    8.32                                            ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.98(3H,t), 1.08(3H,d), 1.19(3H,d), 1.42(9H,s), 3.15(1H,m), 3.88(3H,s), 4.09(2H,t), 4.61(2H,q), 5.64(2H,q), 6.16(1H,s), 6.79-7.01(3H,m), 7.18-7.37(3H,m), 7.59(1H,td), 8.33(1H,dd).

IR (KBr): 3450, 2978, 2936, 1721, 1682, 1638, 1605, 1574, 1510, 1460 cm⁻¹.

Example 23 Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 37) ##STR65##

The compound (0.15 g, 0.23 mmol.) obtained in Example 22 was dissolved in dichloromethan and was stirred with trifuluoroacetic acid for 1 hour at room temperature. The reaction mixture was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of isopropyl alkohol and isopropyl ether to give 0.12 g (yield 86%) of pale yellow powdery crystals, m.p. 214°-216° C. Elemental analysis of the product is shown in Table 29, The NMR spectrum and IR spectrum of the compound were as follows.

                  TABLE 29                                                         ______________________________________                                         Elemental Analysis for C.sub.32 H.sub.30 N.sub.4 O.sub.6.0.5H.sub.2 O                 C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   60.46         4.69    8.55                                            Found    60.14         4.93    8.80                                            ______________________________________                                    

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 0.79(3H,t), 0.99(3H,d), 1.13(3H,d), 3.10(1H,m), 3.89(3H,s), 4.00(2H,t), 4.55(2H,q), 5.53(2H,q), 5.92(1H,s), 6.79-6.92(2H,m), 7.05(1H,d), 7.24(1H,t), 7.37(1H,t), 7.49(1H,d), 7.68(1H,t), 8.13(1H,d), 12.18(1H,br).

IR (KBr): 3444, 2972, 2936, 1719, 1680, 1603, 1574, 1492, 1462 cm⁻¹.

Example 24

Using compounds wherein the substituent at 3-position is --CH₂ COO(t-C₄ H₉). the method described in Example 23 was repeated. Compounds thus obtained (Chemicl Formula 38) are listed in Table 30.

                                      TABLE 30                                     __________________________________________________________________________      ##STR66##                                                                     Ex. 24                                                                              1-substit.                                                                              5-substit.                                                                             6-substit.                                                                               7-substit.                                                                             Yield                                                                               m.p.                              Cpd. No.                                                                            (R.sup.1)                                                                               (QR.sup.3)                                                                             (R.sup.4) (R.sup.5)                                                                              (%)  (°C.)                      __________________________________________________________________________     1    2-methoxy-benzyl                                                                        2-(4-quinolonyl)                                                                       N-ethyl-carbamoyl                                                                        isopropyl                                                                              92   206-207                           2    "        "       carbamoyl "       46   >300                              3    2-methoxy-phenyl                                                                        "       carboxyl  "       46   >300                              4    2-methoxy-benzyl                                                                        2-quinolyl                                                                             ethoxycarbonyl                                                                           3,4-methylene-                                                                         97   145-147                                                           dioxy-phenyl                                   5    "        "       "         phenyl  90   215-217                           6    "        "       "         methyl  50   112-113                           7    "        "       carboxyl  3,4-methylene-                                                                         43   202-204                                                           dioxyphenyl                                    8    "        "       "         phenyl  74   204-206                           9    "        "       "         methyl  93   245-246                           10   "        2-(4-quinolonyl)                                                                       "         "       65   >300                              11   "        "       "         phenyl  58   >300                              __________________________________________________________________________

Example 25 Production of Ethyl [2,4(1H,3H)-dioxo-6-isobutoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 39) ##STR67##

The compound (Compound No. 1: 0.26 g, 0.44 mmol.) obtained in Example 17 was dissolved in dimethylformamide and was stirred with with isobutylbromide (0.14 ml, 1.81 mmol) and potassium carbonate (0.19 g, 1.36 mmol) for 24 hours at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, and was subjected to distribution in ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.21 g (yield 75%) of a colorless amorphous product. Elemental analysts of the product is shown in Table 81. The NMR spectrum and IR spectrum of the compound were as follows.

                  TABLE 31                                                         ______________________________________                                         Elemental Analysis for C.sub.38 H.sub.33 N.sub.4 O.sub.7                              C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   67.70         6.00    8.77                                            Found    67.67         6.22    8.59                                            ______________________________________                                    

¹ H-NMR (200 MHz, CDCl₃) δ ppm: 0.66(6H,d), 1.14(6H,d), 1.23(3H,t), 1.55(1H,m), 3.14(1H,m), 3.53(2H,d), 3.91(3H,s), 4.14(2H,q), 4.68(2H,s), 5.69(2H,s), 6.86-7.00(3H,m), 7.21(1H,td), 7.50(1H,d), 7.56(1H,t), 7.71(1H,td), 7.86(1H,d), 8.04(1H,d), 8.19(1H,d).

IR (KBr): 3456, 2976, 2968, 1721, 1678, 1574, 1495 cm⁻¹.

Example 26

Using the compounds obtained in Example 16 and 17, the method described in Example 25 was repeated. The compounds thus obtained (Chemical Formula 40) were listed in Table 32.

                  TABLE 32                                                         ______________________________________                                          ##STR68##                                                                     Ex. 26        6-          7-sub                                                Cpd.          substit.    stit.   Yield m.p.                                   No.   R.sup.2 (R.sup.4)   (R.sup.5)                                                                              (%)   (°C.)                           ______________________________________                                         1     ethyl   isopropoxy- iso-   25     powder                                               carbonyl    propyl                                               2     "       cyclohexyl  iso-   79     "                                                    oxy-carbonyl                                                                               propyl                                               3     "       cyclohexyl-met                                                                             iso-   73     "                                                    hoxy-carbonyl                                                                              propyl                                               4     "       benzyloxy-  iso-   73     "                                                    carbonyl    propyl                                               5     "       2-quinolylmeth                                                                             iso-   88     "                                                    oxy-carbonyl                                                                               propyl                                               6     "       carboxy-    iso-   80     "                                                    methoxy     propyl                                                             carbonyl                                                         7     "       methoxy-    iso-   64     "                                                    carbonyl    propyl                                               8     "       ethoxycarbonyl                                                                             iso-   87     "                                                                propyl                                               9     "       2-cyanoethoxy-                                                                             3,4-meth                                                                              86     "                                                    carbonyl    ylenedio                                                                       xyphenyl                                             10    t-butyl ethoxycarbonyl                                                                             methyl 87     "                                      11    "       "           phenyl 53     "                                      12    "       "           3,4-meth                                                                              86     "                                                                ylenedio                                                                       yphenyl                                              ______________________________________                                    

Example 27 Production of 2,4(1H,3H)-dioxo-6-isobutoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 41) ##STR69##

The compound (0.19 g, 0.30 mmol.) obtained in Example 25 was dissolved in the mixed solvent of methanol (2.0 ml) and tetrahydrofuran (2.0 ml), to which was added a 2N aqueous solution of sodium hydroxide (0.60 ml, 1.2 mmol), and the mixture was stirred for 110 minutes at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of isopropanol and hexane to give 0.11 g (yield 61%) of colorless powdery crystals, m.p. 224°-225° C. Elemental analysis of the product is shown in Table 33. The NMR spectrum and IR spectrum of the compound were as follows.

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 0.57(6H, d), 1.03(6H,d), 1.38(1H,m), 3.10(1H,m), 3.50(2H,br), 3.90(3H,s), 4.50(2H,s), 5.54(2H,s), 6.83(1H,t), 6.94(1H,d), 7.06(1H,d), 7.24(1H,t), 7.56(1H,d), 7.65(1H,t), 7.78(1H,t), 7.90(1H,d), 8.02(1H,d), 8.34(1H,d).

IR (KBr): 3480, 2970, 1717, 1665, 1574, 1466 cm⁻¹.

                  TABLE 33                                                         ______________________________________                                         Elemental Analysis for C.sub.34 H.sub.34 N.sub.4 O.sub.7.0.5C.sub.3            H.sub.8 O.0.5H.sub.2 O                                                                C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   65.17         6.09    8.56                                            Found    65.04         6.21    8.54                                            ______________________________________                                    

Example 28

Using the compounds obtained in Example 2 (Comp. No. 27,28) and Example 26, the method described in Example 27 was repeated. The compounds thus obtained (Chemical Formula 42) were listed in Table 34.

                  TABLE 34                                                         ______________________________________                                          ##STR70##                                                                     Ex. 28                                                                         Cpd.  5-substit. 6-substit.    Yield  m.p.                                     No.   (QR.sup.3) (R.sup.4)     (%)    (°C.)                             ______________________________________                                         1     2-quinolyl isopropoxy-   61     224-225                                                   carbonyl                                                      2     "          cyclohexyl-   75     218-220                                                   oxy-carbony                                                   3     "          cyclohexyl-meth-                                                                             32     116-118                                                   oxy-carbonyl                                                  4     "          benzyloxy-    95     108-110                                                   carbonyl                                                      5     "          2-quinolylmeth-                                                                              16     133-135                                                   oxy-carbonyl                                                  6     "          carboxymethoxy-                                                                              93     powder                                                    carbonyl                                                      7     "          methoxy-carbonyl                                                                             80     >300                                     8     "          ethoxycarbonyl                                                                               86     powder                                   9     "          "             48     155-157                                  10    3,4-dimethoxy                                                                             "             79     135-136                                        phenyl                                                                   ______________________________________                                    

Example 29

Production of 2,4(1H,3H)-dioxo-6-cyanoethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine-3-acetic Acid (Chemical Formula 43) ##STR71##

The compound (0.30 g, 0.45 mmol.) obtained in Example 3 was dissolved in dichloromethan (3.0 ml) and was stirred with trifuluoroacetic acid (1 ml) for 4.5 hours at room temperature. The reaction mixture was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.31 g of a pale yellow powdery crystals. The crystals were recrystallized from mixed solvent of ethylacetate and hexane to give 0.21 g (yield 78%) of colorless powdery crystals, m.p. 115°-116° C. Elemental analysis of the product is shown in Table 35. The NMR spectrum and IR spectrum of the compound were as follows.

                  TABLE 35                                                         ______________________________________                                         Elemental Analysis for C.sub.33 H.sub.29 N.sub.5 O.sub.7 :0.5H.sub.2           O:0.5CF.sub.3 COOH                                                                    C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   60.62         4.56    10.40                                           Found    60.86         4.86    9.93                                            ______________________________________                                    

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 1.06(6H,d), 2.50(2H,t), 3.78(2H,t), 3.13(1H,m), 3.91(3H,s), 4.50(2H,s), 5.55(2H,s), 6.84(1H,t), 6.95(1H,d), 7.05(1H,d), 7.21(1H,t), 7.59(1H,d), 7.67(1H,t), 7.79(1H,t), 7.97(1H,d), 8.04(1H,d), 8.35(1H,d).

IR (KBr): 3438, 2972, 2270, 1719, 1676, 1574, 1495, 1466 cm⁻¹.

Example 30

Using the compounds obtained in Example 4 (Compd. No. 1) and Example 26 (Compd. Nos. 10-12), the method described in Example 29 was repeated. The compounds thus obtained (Chemical Formula 44) were listed in Table 36.

                  TABLE 36                                                         ______________________________________                                          ##STR72##                                                                     Ex. 30                                                                               5-subs  6-          7-sub                                                Cpd.  tit.    substit.    stit.  Yield  m.p.                                   No.   (QR.sup.3)                                                                             (R.sup.4)   (R.sup.5)                                                                             (%)    (°C.)                           ______________________________________                                         1     4-      2-cyanoethoxy                                                                              iso-   73     213-215                                      tolyl   carbonyl    propyl                                               2     2-quin  ethoxycarbonyl                                                                             methyl 50     112-113                                      olyl                                                                     3     2-quin  cyclohexyl-met                                                                             phenyl 90     215-217                                      olyl    hoxy-carbonyl                                                    4     2-quin  benzyloxy-  3,4-meth                                                                              97     145-147                                      olyl    carbonyl    ylendiox                                                                       yphenyl                                              ______________________________________                                    

Example 31 Production of Ethyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 45) ##STR73##

The acetonitrile solution (15 ml) containing the compound (150 mg, 0.25 mmol.) obtained in Reference Example 13, 2N aqueous solution of potassium carbonate (1.25 ml, 2.50 mmol) and water (1.5 ml) was stirred for 30 minutes at a temperature of 50° C. To the reaction mixture was added 1N HCl (5 ml), which was subjected to distribution to ethyl acetate and saturated aqueous solution of sodium chloride.

The organic layer was dried with MgSO₄, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropanol to give 83 mg (yield 54%) of colorless powdery product, m.p. 167°-170° C. Elemental analysis of the product is shown in Table 37. The NMR spectrum, IR spectrum and MS spectrum of the compound were as follows.

¹ H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.03(6H,d), 1.15(3H,t), 2.59(3H,s), 3.16-3.24(1H,m), 4.11(2H,q), 4.59(1H,d) 4.69(1H,d), 5.53(2H,s), 6.29(1H,s), 6.86(1H,d), 7.09(1H,t) 7.29(1H,t), 7.41(1H,d), 7.50(1H,t), 7.63(1H,d), 7.79(1H,t), 8.21(1H,d), 12.90(1H,bds).

IR (KBr): 3428, 1721, 1678, 1574, 1491, 1369 cm⁻¹.

FAB-MS m/z: 615.1(MH+).

                  TABLE 37                                                         ______________________________________                                         Elemental Analysis for C.sub.32 H.sub.30 N.sub.4 O.sub.7 S.0.5CHCl.sub.3              C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   57.88         4.56    8.31                                            Found    57.73         4.51    8.42                                            ______________________________________                                    

Example 32

Using the compounds obtained in Reference Example 14 the method described in Example 31 was repeated. The compounds thus obtained (Chemical Formula 46) were listed in Table 38.

                  TABLE 38                                                         ______________________________________                                          ##STR74##                                                                     Ex. 32               7-sub                                                     Cpd.  1-substit.     stit.    Yield  m.p.                                      No.   (R.sup.4)      (R.sup.5)                                                                               (%)    (°C.)                              ______________________________________                                         1     2,3-dimethoxy-benzyl                                                                          iso-     67     245-250                                                        propyl                                                    2     2,3,4-trimethoxy-                                                                             iso-     68     158-161                                         benzyl         propyl                                                    ______________________________________                                    

Example 33

Production of t-Butyl [2,4(1H,3H)-dioxo-6-carbamoyl-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 47) ##STR75##

The compound (500 mg, 0.82 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0.60 ml, 8.20 mmol), and the mixture was heated for 30 minutes under reflux. The reaction mixture was cooled and concentrated to dryness.

The residue was suspended in a mixed solvent of tetrahydrofuran (5 ml) and dimethylacetamide (20 ml), and then was stirred with 25% aqueous ammonia (10 ml) for 15 minutes at room temperature. The reaction mixture was poured into ice-water and was adjusted to pH ranging from 1 to 2 with 1N HCl, which was then subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 310 mg (yield 61%) of colorless powder. The powder thus obtained were recrystallized from mixed solvent of iso-propanol and isopropyl ether to give 170 mg (yield 33%) of colorless powdery crystals, m.p. more than 300° C. The elemental analysis values were shown in Table 39. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

¹ H-NMR (200 MHz, DMSO-d₆) δ ppm: 1.01(3H,d), 1.13(3H,d), 1.37(9H,s), 3.20(1H,m), 3.90(3H,s), 4.53(2H,s), 5.53(2H,s), 6.06(1H,s), 6.83-6.89(2H,m), 7.06(1H,d), 7.23(1H,td), 7.32(1H,t), 7.44(1H,d), 7.63(1H,t), 7.75(1H,br), 7.95(1H,br), 8.11(1H,d), 11.82(1H,br).

IR (KBr): 3428, 1721, 1678, 1638, 1605, 1572, 1512, 1475 cm⁻¹.

                  TABLE 39                                                         ______________________________________                                         Elemental Analysis for C.sub.34 H.sub.35 N.sub.5 O.sub.7.H.sub.2 O                    C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   63.44         5.79    10.88                                           Found    63.41         5.80    10.93                                           ______________________________________                                    

Example 34

Using the compounds obtained in Example 16, the method described in Example 33 was repeated, while employing 70% aqueous solution of ethylamine in place of 25% aqueous ammonia. The compound thus obtained (Chemical Formula 48) was listed in Table 40.

                  TABLE 40                                                         ______________________________________                                          ##STR76##                                                                     Ex. 34                                                                         Cpd.           5-substit.                                                                               6-substit.                                                                             Yield  m.p.                                   No.   (R.sup.2)                                                                               (QR.sup.3)                                                                               (R.sup.4)                                                                              (%)    (°C.)                           ______________________________________                                         1     t-butyl  2-(4-quino                                                                               N-ethyl-                                                                               20     172-173                                               lonyl)    carbamoyl                                             ______________________________________                                    

Example 35 Production of t-Butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxbenzyl)-5-(quinoline-1-oxide-2-yl)pyrido[2,3-d]pyrimidine]-3-acetate (Chemical Formula 49) ##STR77##

The compound (300 mg, 0.49 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added m-chlorobenzoyl hydroperoxide (0.25 g), and the mixture was stirred for 21 hours at room temperature. To the reaction mixture was added isopropyl ether (80 ml) to give 200 mg (yield 65%) of colorless powdery crystals, m.p. 176°-178° C. The elemental analysis values were shown in Table 41. The NMR spectrum and IR spectrum of thus obtained compound are as follows.

¹ H-NMR (200 MHz, DMSO-d⁶) δ ppm: 1.07(6H,d), 1.34(9H,s), 3.33(1H,m), 3.90(3H,s), 4.44(2H,s), 5.53(2H,s), 6.79-6.90(2H,m), 7.05(1H,d), 7.24(1H, td), 7.43(1H,d), 7.80-7.97(3H,m), 8.12(1H,d), 8.49(1H,d).

IR (KBr): 3445, 2974, 2372, 1719, 1673, 1572, 1460 cm⁻¹.

                  TABLE 41                                                         ______________________________________                                         Elemental Analysis for C.sub.34 H.sub.34 N.sub.4 O.sub.8.25H.sub.2 O                  C (%)       H (%)   N (%)                                               ______________________________________                                         Calcd.   62.91         5.67    8.63                                            Found    62.91         5.42    8.24                                            ______________________________________                                    

Example 36

Using the compounds obtained in Example 17 the (Comp. No. 15) method described in Example 35 was repeated. The compound thus obtained (Chemical Formula 50) was listed in Table 42.

                  TABLE 42                                                         ______________________________________                                          ##STR78##                                                                     Ex. 36                                                                         Cpd.          5-substit.      Yield  m.p.                                      No.    (R.sup.2)                                                                             (QR.sup.3)      (%)    (°C.)                              ______________________________________                                         1      ethyl  quinoline-1-oxide-3-yl                                                                         12     powder                                    ______________________________________                                    

Example 37 Formulation of Tablets Containing the Compound of This Invention as Effective Component (1)

Using 100 mg of the compound of compound number 2 in Example 19 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process.

Example 38 Formulation of Tablets Containing the Compound of This Invention as Effective Component (2)

Using 100 mg of the compound of Example 10 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process.

Example 39 Formulation of Tablets Containing the Compound of This Invention as Effective Component (3)

Using 100 mg of the compound of Example 12 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process.

Example 40

Formulation of Tablets Containing the Compound of This Invention as Effective Component (4)

Using 100 mg of the compound of Example 20 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process.

Example 41

Formulation of Tablets Containing the Compound of This Invention as Effective Component (5)

Using 100 mg of the compound of compound number 9 obtained in Example 21 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process.

Example 42 Formulation of Injection Containing the Compound of This Invention as Effective Component (1)

In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of compound number 2 obtained in Example 19 of the present invention. The solution is adjusted to pH 7.6 with a 0.1M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 μm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial.

Example 43 Formulation of Injection Containing the Compound of This Invention as Effective Component (2)

In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 10 of the present invention. The solution is adjusted to pH 7.6 with a 0.1M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 μm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial.

Example 44 Formulation of Injection Containing the Compound of This Invention as Effective Component (3)

In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 12 of the present invention. The solution is adjusted to pH 7.6 with a 0.1M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 μm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial.

Example 45 Formulation of Injection Containing the Compound of This Invention as Effective Component (4)

In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 20 of the present invention. The solution is adjusted to pH 7.6 with a 0.1M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 μm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial.

Example 46 Formulation of Injection Containing the Compound of This Invention as Effective Component (5)

In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of compound number 9 obtained in Example 21 of the present invention. The solution is adjusted to pH 7.6 with a 0.1M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 μm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial.

[Pharmacological Experiment--1] Endothelin Receptor-Assay

Endothelin-A receptors was prepared by diluting a fraction of porcine cardiac ventricular muscle membrane with an assay buffer [20 mM Tris-HCl, 2 mM EGTA (ethyleneglycol bis(2-aminoethylether) tetra acetic acid), 5 mM magnesium acetate, 0.1% BSA (bovine serum albumin), 0.03% NAN₃, 0.5 mM PMSF (phenyl methyl sulfonyl fluoride), 20 μg/ml leupeptin, 4 μg/ml E-64 (products of the Peptide Institute), 1 μg/ml pepstatin, (pH 7.2)] to make a solution of the fraction of porcine cardiac ventricular membrane (12 μg/ml).

Endothelin-B receptor was prepared by diluting a fraction of bovine cerebral membrane with the same assay buffer as mentioned above to make a solution having a concentration of 180 μg/ml.

To 100 μl of each portion was added 5 nM [¹²⁵ I] endothelin-1 (2 μl). A dimethylsulfoxide solution (3 μl) of the sample was added thereto and incubated at 25° C. for 60 minutes.

And, to determine the maximum binding amount (B₀) and non-specific binding amount (NSB), lots to which a dimethyl sulfoxide solution (3 μl) or a dimethyl sulfoxide solution (3 μl) containing endothelin-1 (10⁻⁵ M) was added were also incubated.

These lots were supplemented with 0.05% CHAPS (3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate)-assay buffer (1.5 ml), subjected to filtration through a glass fiber filter GF/F (trade name; product of Wattman Ltd. (England)), and then washed with the same buffer (1.5 ml).

Radioactivity on the filter was counted in a gamma-counter to determine the Percent Maximum Binding (PMB) in accordance with the following calculation formula.

The concentration causing PMB=50% was determined as IC₅₀ value. IC₅₀ values of some of the compounds of this invention, synthesized in the above-mentioned examples, are shown in Table 43.

    PMB=[(B-NSB)/(B.sub.0 -NSB)]×100

                  TABLE 43                                                         ______________________________________                                                    IC.sub.50  value: μM                                                          Endothelin-A                                                                              Endothelin-B                                           Compound     Receptor   Receptor                                               No.          (porcine)  (bovine)                                               ______________________________________                                         Cpd. of      11         64                                                     Ex. 10                                                                         Cpd. of      18         130                                                    Ex. 12                                                                         ______________________________________                                    

[Pharmacological Experiment--2] Endothelin Receptor-Assay

Endothelin (ET) receptors were prepared by diluting fractions of insect cell (Sf9) membrane having human endothelin-A (ETA) receptors or human endothelin-B (ETB) receptors appeared, with an assay buffer [20 mM Tris-HCl, 2 mM EGTA (ethyleneglycol bis(2-aminoethylether) tetra acetic acid), 5 mM magnesium acetate, 0.1% BSA (bovine serum albumin), 0.03% NAN₃, 0.5 mM PMS F (phenyl methyl sulfonyl fluoride), 20 μg/ml leupeptin, 4 μg/ml E-64 (products of the Peptide Institute), 1 μg/ml pepstatin, (pH 7.2)] respectively in a concentration of 1.4 μg/ml in the former case and 0.7 μg/ml in the latter case.

To 100 μl of each portion was added 5 nM [¹²⁵ I] endothelin-1 (2 μl). A dimethylsulfoxide solution (3 μl) of the sample was added thereto and incubated at 25° C. for 60 minutes.

And, to determine the maximum binding amount (B₀) and non-specific binding amount (NSB), lots to which a dimethyl sulfoxide solution (3 μl) or a dimethyl sulfoxide solution (3 μl) containing endothelin-1 (10⁻⁵ M) had been added, were also incubated.

These lots were supplemented with 0.05% CHAPS (3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate)-assay buffer (1.5 ml), subjected to filtration through a glass fiber filter GF/F (trade name; product of Wattman Ltd. (England)), and then washed with the same buffer (1.5 ml).

Radioactivity on the filter was counted in a gamma-counter to determine the Percent Maximum Binding (PMB) in accordance with the aforesaid calculation formula. The concentration causing PMB=50% was determined as IC₅₀ value. IC₅₀ values of some of the compounds of this invention, synthesized in the above-mentioned examples, are shown in Table 44.

                  TABLE 44                                                         ______________________________________                                                        IC.sub.50  value: μM                                                          Endothelin-A                                                                               Endothelin-B                                      Compound No.     Receptor    Receptor                                          Example No.                                                                             Compound No.                                                                               (human)     (human)                                       ______________________________________                                         10                   11          --                                            12                   22          --                                            14                   3.7         67                                            15       4           0.89        95                                            16                   1.6         69                                            17       1           0.71        19                                            18                   0.15        69                                            19       2           0.07        65                                            19       5           0.98        23                                            20                   0.12        14                                            21       9           0.056       14                                            23                   0.92        4.3                                           27                   4.5         47                                            28       8           1.1         76                                            29                   0.57        95                                            31                   0.12        88                                            ______________________________________                                    

According to the result shown in the table 43 and 44, it has been proved that the compound [A] or its salt of this invention have excellent endothelin receptor antagonistic action to both endothelin-A receptor and endothelin-B receptor.

The compounds of this invention have an endothelin receptor antagonistic action, which are effective as prophylactic and therapeutic agents against acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs.

It is apparent that various modifications may be made in the foumulations and application of the novel compound of this invention, without departing from the invention concept herein, as defined in the following claims. 

We claim:
 1. A pyrido[2,3-d]pyrimidine derivative represented by the formula (A"): ##STR79## wherein n' denotes an integer of 1 to 3; R¹¹¹ is a hydrogen atom; a C₁₋₆ alkyl group; or a phenyl-C₁₋₃ alkyl group optionally substituted by at least one member selected from the group consisting of a C₁₋₆ alkoxy group and a C₁₋₆ alkylthio group;R²¹¹ is a hydrogen atom or a C₁₋₆ alkyl group; R³¹¹ is (1) a phenyl group or naphthyl group optionally substituted by at least one member selected from the group consisting of a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a C₁₋₆ alkoxy group, a halogen atom, nitro group, cyano group and phenyl group; or (2) a pyridyl group, quinolyl group, quinolonyl group or thienyl group optionally substituted by at least one member selected from the group consisting of a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, and hydroxyl group; R⁴¹¹ is --COOR⁶¹¹ wherein R⁶¹¹ is (1) a hydrogen atom; (2) a C₁₋₆ alkyl group optionally substituted by a carboxyl group, a cyano group or a quinolyl group; (3) C₃₋₇ cycloalkyl group; or (4) C₇₋₁₅ aralkyl group or R⁴¹¹ is --CONR⁷¹¹ R⁸¹¹ wherein R⁷¹¹ and R⁸¹¹ independently are a hydrogen atom or C₁₋₆ alkyl group; and R⁵¹¹ is (1) a hydrogen atom; (2) a C₁₋₆ alkyl group; or (3) a phenyl group optionally substituted by a C₁₋₃ alkylenedioxy group; or a salt thereof.
 2. 2,4(1H,3H)-Dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.
 3. 2,4(1H,3H)-Dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.
 4. Ethyl[2,4(1H,3H)-Dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate or its salt.
 5. 2,4(1H,3H)-Dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.
 6. 2,4(1H,3H)-Dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.
 7. A compound selected from the group consisting of2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido [2,3-d]pyrimidine-3-acetic acid, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2,4-dimethoxybenzyl)-5-(2-quinolyl)pyrido [2,3-d]pyrimidine-3-acetic acid, t-butyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolylpyrido[2,3-d]pyrimidine]-3-acetate, ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolylpyrido[2,3-d]pyrimidine]-3-acetate, t-butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate, ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2,4-dimethoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate, 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5- [2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid,
 2. 4(1H,3H)-dioxo-6-isobutoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolylpyrido[2,3-d]pyrimidine-3-acetic acid,2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolylpyrido[2,3-d]pyrimidine-3-acetic acid, 2,4(1H,3H)-dioxo-6-cyanoethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolylpyrido[2,3-d]pyrimidine-3-acetic acid, and ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetate; or a salt thereof.
 8. A pharmaceutical composition useful as an endothelin receptor antagonist comprising, as the effective component, at least one compound selected from pyrido[2,3-d]pyrimidine derivative represented by the formula (A) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
 9. A pharmaceutical composition as claimed in claim 8, wherein the antagonist is an endothelin-A receptor antagonist.
 10. A method for treating a patient suffering from myocardial infarction which comprises administering to said patient an effective daily dosage of between 0.1 and 500 mg per day of the pyrido[2,3-d]pyrimidine derivative of claim 1 or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition containing the derivative as the active component.
 11. A pharmaceutical composition as claimed in claim 9 wherein the antagonist is a therapeutic agent for myocardial infarction.
 12. A method for treating a patient suffering from myocardial infarction which comprises administering to said patient an effective daily dosage of between 0.1 and 500 mg per day of the composition of claim
 9. 13. A pyrido[2,3-d]pyrimidine derivative represented by the formula (A'"): ##STR80## wherein n" denotes an integer of 1 to 3; R¹¹¹¹ is a phenyl-C₁₋₃ alkyl group optionally substituted by at least one member selected from the group consisting of a C₁₋₆ alkoxy group and a C₁₋₆ alkylthio group;R²¹¹¹ is a hydrogen atom or a C₁₋₆ alkyl group; R³¹¹¹ is a quinolyl group or quinolonyl group; R⁴¹¹¹ is a group of the formula: --COOR⁶¹¹ wherein R⁶¹¹ is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by a cyano group; and R⁵¹¹¹ is a C₁₋₆ alkyl group; or a salt thereof. 